Systems and methods for nerve conduction block

ABSTRACT

Disclosed herein are systems and methods for nerve conduction block. The systems and methods can utilize at least one rechargeable electrode. The methods can include delivering a first direct current with a first polarity to an electrode proximate nervous tissue sufficient to at least partially block conduction in the nervous tissue.

INCORPORATION BY REFERENCE

This application is the U.S. National Phase under 35 U.S.C. § 371 ofInternational Application No. PCT/US2019/040189, filed Jul. 1, 2019,which claims the benefit under 35 U.S.C. § 119(e) as a nonprovisionalapplication of U.S. Prov. App. No. 62/692,857, filed on Jul. 1, 2018,which are each incorporated by reference in their entireties.

BACKGROUND Field of the Invention

This application relates, in some embodiments, to facilitating block ofbiological signals through nerve tissue.

The gate control theory of pain was developed in the 1960s and led tothe advent of stimulation-based pain management therapies to reduce paininputs from reaching the brain by selectively stimulatingnon-nociceptive fibers (non-pain transmitting fibers) in the spinal cordto inhibit transmission of pain stimuli to the brain (See Mendell,Constructing and Deconstructing the Gate Theory of Pain, Pain, 2014February 155(2): 210-216). Current stimulation systems for spinal cordstimulation (SCS), which act on this gate control theory to indirectlyreduce pain, typically have relied on stimulation signals in the <100 Hzfrequency range, and recently in the kHz frequency range. Stimulation ofthe dorsal root ganglia, DRG, in a similar frequency range has also beenemployed to reduce segmental pain through the same mechanism.

However, technologies based on this premise are not perfect as paintransmission inhibition is not complete and side effects such asparesthesia can be uncomfortable for patients. Therefore, it isdesirable to have systems and methods of treating pain which directlyblock pain fibers from transmitting pain signals, rather than indirectlyreducing pain signals through gate-theory activation of non-nociceptivefibers. Furthermore, block of neural tissue or neural activity has beenimplicated in not only affecting pain but also in the management ofmovement disorders, psychiatric disorders, cardiovascular health, aswell as management of disease states such as diabetes.

SUMMARY

In some embodiments, a system to modulate the action potentialtransmission along a nerve body includes an electron to ion currentconversion cell (EICCC) which comprises an electrode at which anelectrochemical process occurs to generate current in the form of ionsto change the electrical potential around the nerve and modulate thenerve membrane potential.

In some embodiments, a system to modulate the action potentialtransmission along a nerve body includes an electron to ion currentconversion cell which comprises an electrode at which a capacitivecharging process occurs to generate current in the form of ions tochange the charge density around the nerve and modulate the nervemembrane potential.

In some embodiments, a system to modulate the stimulus transmissionalong a nerve body includes an electron to ion current conversion cellwhich comprises an electrode at which an electrochemical process occursto generate current in the form of ions to change the charge densityaround the nerve and modulate the nerve membrane potential.

In some embodiments, a system to modulate the stimulus transmissionalong a nerve body includes an electron to ion current conversion cellwhich comprises an electrode at which an electrochemical process andcapacitive charging process occur to generate current in the form ofions to change the charge density around the nerve and modulate thenerve membrane potential.

In some embodiments, the system modulates the electrical potential nearthe nerve to put the nerve tissue in a blocked state.

In some embodiments, the system puts the target nerve(s) in a state ofacute nerve block.

In some embodiments, the system puts the target nerve(s) in a state ofchronic nerve block.

In some embodiments, the system modulates the electrical potential toput the nerve tissue into a suppressed state.

In some embodiments, the system puts the target nerve(s) in a state ofacute nerve suppression.

In some embodiments, the system puts the target nerve(s) in a state ofnerve hypersuppression.

In some embodiments, the electrode comprises an electrode material ofsilver, silver-chloride (Ag/AgCl).

In some embodiments, the electrode comprises an electrode material ofsilver (Ag).

In some embodiments, the electrode comprises an electrode material ofsilver-chloride (AgCl).

In some embodiments, the masses of the electrode constituent materialsare maintained in a specified range.

In some embodiments, the electrochemical processes which occur at theelectrode are reversible.

In some embodiments, the electrode is sacrificial and cannot berestored.

In some embodiments, the system comprises an electrode immersed inelectrolyte and fluidly and electronically coupled to an ion conductorin electrical contact with the nerve tissue.

In some embodiments, the ion conductor comprises a hydrogel material.

In some embodiments, the system comprises one or more current sourcesthat are connected via a lead to the one or more electrodes.

In some embodiments, the ion conductor includes a proximal layer, e.g.,screen or filter element to selectively sequester electrochemicalprocess byproducts to the electrolyte volume.

In some embodiments, the ion conductor includes a distal screen orfilter element to selectively sequester electrochemical processbyproducts from the nerve tissue.

In some embodiments, the ion conductor includes multiple screen orfilter elements to selectively sequester electrochemical processbyproducts from the nerve tissue.

In some embodiments, the system comprises materials which come incontact with tissue that are biocompatible.

In some embodiments, two or more systems to modulate the stimulustransmission along a nerve body include electron to ion currentconversion cells to change the electrical potential around the nerve andmodulate the nerve membrane potential.

In some embodiments, a method using two or more systems to maintain aconstant nerve block by delivering direct current in the form of ionsincludes operating one system in a blocking mode with current of onepolarity while the other system or systems are run in a mode withcurrent of the opposite polarity.

In some embodiments, a method of delivering a prolonged block to neuraltissue includes an initial delivery of current in the form of ionsproximal to the neural tissue to put the neural tissue into a suppressedstate where block continues after current ceases.

In some embodiments, a method of delivering a prolonged block to neuraltissue includes an initial delivery of current in the form of ionsproximal to the neural tissue to put the neural tissue into a suppressedstate where block continues after current ceases with subsequent currentdelivery to maintain the nerve in its suppressed state.

In some embodiments, a method of delivering a prolonged block to neuraltissue includes an initial delivery of current in the form of ionsproximal to the neural tissue to put the neural tissue into a suppressedstate where block continues after current ceases with subsequent currentdelivery to maintain the nerve in its suppressed state whereby currentof the opposite polarity between current delivery phases does not impactthe nerve suppression state.

In some embodiments, a system for accessing and modulating the nervesignal transmission properties of a DRG includes an introducer needlecomprising optionally radiopaque markers and a stylet and an electrodeconfigured to fit within the needle bore. The electrode comprisingstress-relief and securement features such as barbs and leads thatprovide electrical communication with a current source.

In some embodiments, a system for accessing and modulating the nervesignal transmission properties of the spinal cord includes an introducerneedle comprising optionally radiopaque markers and a stylet and anelectrode configured to fit within the needle bore. The electrodecomprising stress-relief and securement features such as barbs and leadsthat provide electrical communication with a current source.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of a DRG includes insertion of anintroducer needle into the body cavity to the nerve site, removing astylet, inserting an electrode, securing the electrode at the desiredtissue site, removing the needle, and connecting the EICCC electrodeleads to a current source and delivering a current to put the nerve in astate of suppression.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of the spinal cord includes insertion ofan introducer needle into the body cavity to the nerve site, removing astylet, inserting an electrode, securing the electrode at the desiredtissue site, removing the needle, and connecting the EICCC electrodeleads to a current source and delivering a current to put the nerve in astate of suppression.

In some embodiments, the system includes an external current source.

In some embodiments, the system includes an implantable current source.

In some embodiments, the system includes a programmable current source.

In some embodiments, the system comprises a sensor proximal to the nervetissue to monitor the nerve tissue membrane potential and provide afeedback measurement for the current source.

In some embodiments, the system comprises a sensor that is an electrodethat serves as a reference electrode for the working electrode in theEICCC to monitor the electrode potential.

In some embodiments, a method for maintaining a nerve in a blocked stateis disclosed wherein the nerve membrane potential is monitored and usedas a signal to provide feedback to the current source and current sourcecontroller to enable modulation of the current source output to theelectrode.

In some embodiments, the system for delivery of ion current to neuraltissue comprises a current delivery source, a power supply, electricalconnection to an EICCC with a connector element to which an ionconducting electrode may be connected wherein the system is hermeticallysealed.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the DRG is used to reduce pain due toneuralgias.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the DRG or DRGs is used to reduce paindue to angina.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the DRG or DRGs is used to reduce paindue to ischemic pain.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the DRG or DRGs is used to reduce paindue to complex regional pain syndrome (CPRS).

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the DRG or DRGs is used to reduce painin a specific region of the body.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the DRG or DRGs is used to reduce painin a specific limb of the body.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the DRG or DRGs is used to reduce painin a specific region of a limb of the body.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the DRG or DRGs can delivery differentcurrent signals to different DRGs for improved pain reduction coverage.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the spinal cord includes more than oneelectrode leads.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the spinal cord includes more than oneelectrode leads which include one or more regions that contact tissueand deliver current to the tissue.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the spinal cord includes more than oneelectrode leads at different levels along the spinal cord which includeone or more regions that contact tissue and deliver current to thetissue.

In some embodiments, the system for accessing and modulating the nervesignal transmission properties of the spinal cord includes more than oneelectrode leads which include one or more regions that contact tissueand deliver current to the tissue and can be individually adjusted todeliver the desired current and electric field to the tissue.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of the spinal cord includes generatingpain relief as part of a peri-procedural pain block.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of the spinal cord includes generatingpain relief as part of a peri-procedural pain block that is quicklyreversible.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of peripheral nerves to generate painrelief includes delivering direct current with an EICCC to peripheralnerve tissue to reduce focal pain.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of peripheral nerves to generate painrelief includes delivering direct current with an EICCC to peripheralnerve tissue to reduce phantom limb pain.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of peripheral nerves to generate painrelief includes delivering direct current with an EICCC to peripheralnerve tissue to reduce neuroma pain.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of peripheral nerves to generate painrelief includes delivering direct current with an EICCC to peripheralnerve tissue to reduce neuralgia pain.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of renal nerves includes reducingactivity of the sympathetic nervous system to reduce hypertension.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of the sympathetic ganglia includesreducing activity of the sympathetic cervical ganglia to reduce heartfailure progression.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of the sympathetic ganglia includesreducing activity of the sympathetic cervical ganglia to reduce orprevent tachycardia.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of the vagus nerve includes reducingactivity of the vagus nerve to increase heart rate.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of the vagus nerves innervating thestomach includes reducing activity of the vagus nerve to increasesatiety and satiation.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of hepatic nerves includes reducingactivity of the sympathetic nervous system to increase insulinproduction.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of hepatic nerves includes reducingactivity of the sympathetic nervous system to reduce insulin resistance.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of brain tissue includes accessing thedesired region of the brain and reducing neural tissue activity to treatmovement disorders.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of brain tissue includes accessing thedesired region of the brain and reducing neural tissue activity to treatpsychiatric disorders.

In some embodiments, a method for accessing and modulating the nervesignal transmission properties of brain tissue includes accessing thedesired region of the brain and reducing neural tissue activity to treatchronic pain.

In some embodiments, disclosed herein is a system for nerve block of apatient utilizing a renewable electrode. The system can include a directcurrent generator, and/or at least one electrode comprising silverchloride. The system can also include a controller configured to signalthe direct current generator to deliver a first direct current with afirst polarity through the electrode sufficient to block conduction in anerve, and/or decrease an amount of the silver chloride in the electrodethereby forming solid silver and chloride ions. The controller can alsobe configured to signal the direct current generator to deliver a seconddirect current with a second polarity through the electrode sufficientto increase the amount of the silver chloride, thereby renewing theelectrode. The system can also include a nerve interface spaced apartfrom the electrode by a selective barrier. The selective barrier canalso be configured to allow chloride ions through the barrier toward thenerve interface to block the nerve. The system can also include a sensorconfigured to determine whether a reaction, such as a predominantlysilver/silver chloride reaction is occurring. The controller can befurther configured to receive data from the sensor and discontinue ormodulate at least one of the first direct current signal or the seconddirect current signal when water is being electrolyzed. The selectivebarrier can be further configured to prevent silver ions from passingthrough the barrier toward the nerve interface. The electrode can behoused in an insulated enclosure. The selective barrier can include anion exchange membrane, and/or a hydrogel. The system can be devoid ofany mechanically moving parts in some cases. The controller can beconfigured to deliver the first direct current such that the amount ofsilver chloride decreased is greater than a surface area of theelectrode prior to delivery of the first direct current. The controllercan also be configured to deliver the first direct current such that theamount of silver chloride decreased is greater than, such as about1.25×, 1.5×, 2×, 3×, 4×, 5×, 10×, 15×, 20×, 50×, 100×, 1,000×, or morean amount capable of evenly covering a surface area, such as the entirefunctional surface area of the electrode prior to delivery of the firstdirect current, or ranges including any two of the aforementionedvalues.

In some embodiments, also disclosed herein is a system for nerve blockof a patient utilizing a renewable electrode. The system can include oneor more of: a direct current generator; at least one electrodecomprising a solid component, an ionic component, and a nerve interfacedirectly adjacent the ionic component; a controller configured to signalthe direct current generator to: deliver a first direct current with afirst polarity through the electrode sufficient to block conduction in anerve and decrease an amount of the solid component; and/or deliver asecond direct current with a second polarity through the electrodesufficient to increase the amount of the solid component, therebyrenewing the electrode. The system can also include one or more sensorsconfigured to determine whether a predominantly solid component/ioniccomponent reaction is occurring. The controller can be furtherconfigured to receive data from the sensor and discontinue or modulateat least one of the first direct current signal or the second directcurrent signal when water is being electrolyzed. The electrode, or aplurality of electrodes, can be housed in an insulated enclosure, suchas the same or a different enclosure. The electrode can also include alayer, such as a selective barrier spaced between the ionic componentand the nerve. The layer can be configured to selectively allownegatively charged ions of the ionic component to pass through the layerand toward the nerve, and prevent positively charged ions of the ioniccomponent from passing through the layer toward the nerve. The systemcan be devoid of any mechanically moving parts. The nerve interface canbe spaced apart from the electrode by one or more of a gel, a hydrogel,and an ion conductive polymer. The electrode can be partially orcompletely surrounded by a solution, such as an electrolyte solution,e.g., isotonic saline. The solid component can include silver, and/orthe ionic component can include silver chloride. The controller can beconfigured to deliver the first direct current such that the amount ofsolid component decreased is greater than a surface area of the solidcomponent. The controller can also be configured to maintain the nervein a hypersuppressed state at least partially preventing conduction ofthe nerve for at least about 10 minutes or more after cessation ofdelivering of the first direct current.

In some embodiments, also disclosed herein is a method for nerve blockof a patient utilizing a renewable electrode. The method can include oneor more of delivering a first direct current of a first polarity throughan electrode comprising a first component proximate a nerve sufficientto block conduction in the nerve; and delivering a second direct currentof a second polarity opposite the first polarity through the electrode.The first direct current can decrease an amount of the first componentof the electrode thereby producing a second component different from thesecond component. The second direct current can increase the amount ofthe first component of the electrode and/or decreases the amount of thesecond component to renew the electrode. The method can also dynamicallysensing the amount of the first component or the second component in theelectrode while delivering the first direct current; and ceasingdelivery of the first direct current when the amount of the firstcomponent is sensed to reach a pre-determined threshold value, and/orwhen water is electrolyzed.

Also disclosed herein is a method for extended nerve block utilizing aplurality of renewable electrodes. The method can deliver a first directcurrent with a first polarity through a first electrode proximate anerve sufficient to block conduction in the nerve, the electrodecomprising a solid component and an ionic component; delivering a seconddirect current with a second polarity opposite the first polaritythrough a second electrode spaced axially apart from the first electrodeand proximate the nerve while the nerve is in the hypersuppressed state;and/or reversing the polarities of the first direct current and thesecond direct current, wherein reversing the polarities maintains thenerve in the hypersuppressed state.

In some embodiments, also disclosed herein is a method for extendednerve block utilizing at least one renewable electrode. The method caninclude delivering a first direct current with a first polarity to anelectrode proximate a nerve sufficient to block conduction in the nerve.Delivering the first direct current can place the nerve in ahypersuppressed state at least partially preventing conduction of thenerve after cessation of delivering of the first direct current. Themethod can also include delivering a second direct current with a secondpolarity opposite the first polarity through the electrode entirelywhile the nerve remains in the hypersuppressed state. The electrode canbe, for example, an electrochemical or capacitive electrode. Acapacitive electrode can include tantalum or titanium, for example. Theelectrode can include silver and/or silver chloride in some cases.Delivering the first direct current can change the electrode from afirst configuration to a second configuration, and delivering the seconddirect current transforms the electrode from the second configurationback to the first configuration, or at least closer to the firstconfiguration. The second configuration can include a lower amountand/or a lower charge than a material than the first configuration.

Also disclosed herein is a method for nervous tissue block utilizing atleast one renewable electrode. The method can include delivering a firstdirect current with a first polarity to an electrode proximate nervoustissue sufficient to block conduction in the nervous tissue. Deliveringthe first direct current can place the nervous tissue in ahypersuppressed state at least partially preventing conduction of thenervous tissue after cessation of delivering of the first directcurrent. The method can also include maintaining the nervous tissue inthe hypersuppressed state for at least about 1 minute, 10 minutes, 1hour, 24 hours, or more. The method can also include sensing theconduction ability of the nervous tissue, and/or maintaining the nervoustissue in a hypersuppressed state by delivering a third direct currentthrough the electrode to the nervous tissue after sensing the conductionability of the nervous tissue, wherein the third direct current has thesame polarity as the first direct current. Sensing the conductionability of the nervous tissue can include delivering a stimulus pulse tothe nervous tissue and measuring a compound action potential signal,and/or measuring potential differences via a reference electrode. Thenervous tissue could include one or more of a nerve, such as a spinal,cranial, or peripheral nerve, or brain tissue, dorsal root ganglia,tissue of the spinothalamic tract, autonomic nervous tissue, sympatheticnervous tissue, or parasympathetic nervous tissue. The direct currentcan be therapeutically effective to treat pain, such as acute or chronicpain and/or ischemic pain. The direct current can also betherapeutically effective to treat a psychiatric condition such asdepression, anxiety, obsessive-compulsive disorder, PTSD, mania, orschizophrenia; a movement disorder such as Tourette's syndrome,Parkinson's disease, spasticity, or essential tremor; and/or acardiopulmonary condition such as hypertension, congestive heartfailure, ischemic cardiomyopathy, angina, or an arrhythmia.

Also disclosed herein is a system for extended nerve block utilizing areversible electrode. The system can include one or more of a directcurrent generator; at least one electrode comprising a solid component,an ionic component, and a nerve interface adjacent the ionic component;a controller configured to signal the direct current generator to:deliver a first direct current with a first polarity through theelectrode sufficient to block conduction in a nerve; maintain the nervein a hypersuppressed state at least partially preventing conduction ofthe nerve after cessation of delivering of the first direct current;and/or deliver a second direct current with a second polarity throughthe electrode entirely while the nerve remains in the hypersuppressedstate.

Also disclosed herein is a method for providing extended nerve blockutilizing a renewable electrode. The method can include delivering afirst direct current of a first polarity through an electrode proximatea nerve sufficient to block conduction in the nerve, the electrodecomprising a first component and a second component; hypersuppressingthe nerve to at least partially prevent conduction of the nerve aftercessation of the first direct current; and/or delivering a second directcurrent of a second polarity opposite the first polarity through theelectrode while the nerve is in the hypersuppressed state. The firstdirect current can decrease an amount of the first component andincrease the amount of the second component. The second direct currentcan increase the amount of the first component and decreases the amountof the second component to renew the electrode. In some embodiments, themethod does not fully deplete the first component. The method can alsoinclude sensing the amount of at least one of the first component andthe second component; and ceasing delivering the first direct currentwhen the amount of the first component reaches a predetermined minimumthreshold value. A net charge delivered to the nerve after deliveringthe first direct current and the second direct current can be zero. Thefirst direct current can be an anodic or cathodic current and the seconddirect current can be a cathodic or an anodic current. The method canalso include sensing the conduction ability of the nerve, and/ormaintaining the nerve in a hypersuppressed state by delivering a thirddirect current through the electrode to the nerve after sensing theconduction ability of the nerve, wherein the third direct current hasthe same polarity as the first direct current. Sensing the conductionability of the nerve can include delivering a stimulus pulse to thenerve and measuring a compound action potential signal, and/or measuringpotential differences via reference electrode. In some embodiments,there can be a current-free gap in time in between delivering the firstdirect current of the first polarity and delivering the second directcurrent of the second polarity.

The method can also include delivering at least one, two, or moreadditional cycles of direct current. One cycle can include deliveringthe first direct current of the first polarity and delivering the seconddirect current of the second polarity opposite the first polaritythrough the electrode. The method can also include implanting theelectrode proximate the nerve, percutaneously positioning the electrodeproximate the nerve, and/or transcutaneously positioning the electrodeproximate the nerve. The nerve can be spaced apart from the electrode bya gel, a hydrogel, an ion conductive polymer, and/or a layer. Theelectrode can be partially or completely surrounded by an electrolytesolution, such as an isotonic saline solution.

In some embodiments, disclosed herein is a system for nerve block of apatient utilizing a capacitive rechargeable electrode. The system caninclude any number of: a current generator; at least one implantableelectrode comprising titanium nitride, the at least one electrodeconfigured to be in electrical communication with the current generator;a controller configured to signal the current generator to: generate afirst current with a first polarity proximal to the at least oneelectrode sufficient to at least partially block conduction in a nerve,wherein an amount of stored charge in the at least one electrodedecreases and generates current in an ionic component proximate the atleast one electrode when the electrode is implanted within the patient;and generate a second current with a second polarity proximal to the atleast one electrode sufficient to increase the amount of stored chargein the at least one electrode.

In some embodiments, the system can also include a sensor configured todetermine the state of stored charge of the at least one electrode. Thecontroller can be further configured to receive data from the sensor anddiscontinue at least one of the first current signal or the secondcurrent signal when an amount of water is being electrolyzed.

In some embodiments, the decrease and increase in amount of storedcharge on the at least one electrode can be equal, or unequal.

In some embodiments, the at least one electrode is housed in aninsulated enclosure.

In some embodiments, the titanium nitride comprises porous or fractaltitanium nitride.

In some embodiments, the titanium nitride electrode can be configured todeliver at least about 5,000, 25,000 μC, or more of charge intoexcitable tissue without damaging the excitable tissue.

In some embodiments, the system is devoid of any mechanically movingparts.

In some embodiments, a system for nerve block of a patient utilizing acapacitive rechargeable electrode can include any number of thefollowing features: a current generator; at least one implantableelectrode comprising a high charge density material configured to bespaced apart from a nerve interface by an ionic component, the at leastone implantable electrode configured to be in electrical communicationwith the current generator; and a controller configured to signal thecurrent generator to: generate a first current with a first polarityproximal to the at least one implantable electrode sufficient to atleast partially block conduction in a nerve, wherein an amount of storedcharge in the at least one electrode decreases and generates current inan ionic component proximate the at least one electrode when theelectrode is implanted within the patient; and generate a second currentwith a second polarity proximal to the at least one implantableelectrode sufficient to increase the amount of stored charge of the atleast one implantable electrode.

In some embodiments, a sensor can be configured to determine the stateof charge of the at least one implantable electrode. The controller canbe further configured to receive data from the sensor and discontinue atleast one of the first current or the second current when an amount ofwater is being electrolyzed.

In some embodiments, the decrease and increase in amount of storedcharge on the at least one electrode are not equal.

In some embodiments, the at least one implantable electrode isconfigured to deliver at least about 5,000 μC, 25,000 μC, or more ofcharge into excitable tissue without damaging the excitable tissue.

In some embodiments, the system is devoid of any mechanically movingparts.

In some embodiments, the at least one implantable electrode is at leastpartially surrounded by an electrolyte solution.

In some embodiments, the high charge density material comprises titaniumnitride.

In some embodiments, the controller is configured to maintain the nervein a hypersuppressed state at least partially preventing conduction ofthe nerve for at least about 10 minutes after cessation of delivering ofthe first current.

Also disclosed herein is a method for nerve block of a patient utilizinga rechargeable electrode. The method can include any number of:generating a first current of a first polarity through a titaniumnitride implanted electrode proximate a nerve sufficient to at leastpartially block conduction in the nerve, wherein the electrode generatescurrent in an ionic component proximate the at least one electrodesufficient to create at least a partial block in the nerve and decreasethe amount of stored charge in the implanted electrode; and generating asecond current of a second polarity opposite the first polarity throughthe implanted electrode. The second current can increase the amount ofthe stored charge of the implanted electrode to recharge the implantedelectrode.

In some embodiments, a method can also include dynamically sensing theamount of the stored charge in the implanted electrode while deliveringthe first current; and ceasing delivery of the first current when theamount of the stored charge is sensed to reach a pre-determinedthreshold value.

In some embodiments, a method can also include discontinuing at leastone of the first current signal or the second current signal when anamount of water is being electrolyzed.

In some embodiments, the decrease and increase in amount of storedcharge on the at least one electrode are not equal.

In some embodiments, the decrease and increase in amount of storedcharge on the at least one electrode are equal.

In some embodiments, the at least one electrode is housed in aninsulated enclosure.

In some embodiments, the titanium nitride comprises porous or fractaltitanium nitride.

In some embodiments, the titanium nitride electrode generates currentsufficient to deliver at least about 5,000 μC, 25,000 μC, or more ofcharge into excitable tissue without damaging the excitable tissue.

In some embodiments, the titanium nitride electrode generates currentsufficient to deliver at least about 25,000 μC of charge into excitabletissue without damaging the excitable tissue.

A method for nerve block of a patient utilizing a rechargeableelectrode, comprising: generating a first current of a first polarityproximal to an implanted electrode comprising a high charge densitymaterial proximate a nerve sufficient to at least partially blockconduction in the nerve, wherein the electrode generates current in anionic component proximate the at least one electrode sufficient tocreate at least a partial block in the nerve and decrease the amount ofstored charge in the implanted electrode; generating a second current ofa second polarity opposite the first polarity through the implantedelectrode, wherein the second current increases the amount of the storedcharge of the implanted electrode to recharge the implanted electrode;and dynamically sensing the amount of the stored charge in the electrodewhile delivering the first current; and ceasing delivery of the firstcurrent when the amount of the stored charge is sensed to reach apre-determined threshold value.

In some embodiments, the electrode is created by providing a substratecomprising a high charge density coating material on a surface thereof;and creating a microstructure within the substrate to increase anavailable electrochemical surface area of the high charge densitycoating material.

In some embodiments, the substrate comprises titanium orplatinum-iridium.

In some embodiments, the coating material comprises porous titaniumnitride.

In some embodiments, the high charge density coating material caninclude one or more of: iridium oxide,Poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT),titanium nitride (TiN), fractal titanium nitride, porous titaniumnitride, or a combination thereof.

In some embodiments, the high charge density coating material comprisestitanium nitride.

In some embodiments, creating a microstructure comprises micromachiningthe substrate material.

In some embodiments, micromachining comprises electric dischargemachining.

In some embodiments, creating a microstructure comprises using one ormore of: material etching techniques, pattern masking and etchingtechniques, bead or grit blasting, and surface sanding.

In some embodiments, creating a microstructure comprises lasertexturing.

In some embodiments, laser texturing comprises creating spaced-apartchannels or grooves in the tubular member.

In some embodiments, the channels or grooves comprise a spiral orcircumferential geometry with respect to a long axis of the tubularmember.

In some embodiments, creating a microstructure comprises foaming.

In some embodiments, creating a microstructure comprises sintering.

In some embodiments, creating a microstructure comprises increasing anavailable electrochemical surface area by at least about 2×.

In some embodiments, creating a microstructure comprises increasing anavailable electrochemical surface area by at least about 5×.

In some embodiments, creating a microstructure comprises increasing anavailable electrochemical surface area by at least about 10×.

In some embodiments, the substrate comprises a tubular member.

In some embodiments, the substrate comprises a material sheet.

In some embodiments a current delivery system or method could includeany number of features or combination of features as disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows an embodiment of an EICCC electrode in which an electrodeis immersed in an electrolyte solution which is in contact with anion-conductive material-electrolyte solution interface with anion-conductive material that electrically contacts the nerve tissue N orarea proximal to the nerve tissue N.

FIG. 1B is a graph illustrating by pushing a constant current from thecurrent source, the mass of the AgCl electrode can decrease during acathodic current (reduction reaction) and then increase with an anodiccurrent during an oxidative reaction.

FIG. 1C shows how current being delivered to the electrode cell (EICCC)(top) can be associated with charge delivered to the electrodecell-nerve interface (middle) to provide nerve block (bottom) whileenabling zero net charge transfer with long charge phases, according tosome embodiments of the invention.

In FIG. 1D waveform patterns delivered to an electrode cell tofacilitate nerve block are shown in which current delivered to theelectrode cell is shown along with corresponding nerve block periodsincluding hypersuppression regions in which nerve block occursregardless of current being delivered to the nerve tissue, according tosome embodiments of the invention.

FIG. 1E shows an embodiment of an electron-ion current conversion cell(EICCC) which is connected via an electrically insulated lead to acurrent source.

FIG. 1F illustrates a configuration when the electron current is of onepolarity as designated by the positive axis, the nerve block is shown tobe active and when the polarity of the current is reversed as designatedby the negative axis, the nerve block is shown to be inactive.

FIG. 1G shows a similar configuration to FIG. 1E but with sequestrationscreens that respectively separate the traditional electrode from theion conductor and the ion conductor from the nerve itself.

FIG. 1H illustrates current vs. time and nerve block status vs. timecharts similar to FIG. 1F.

FIG. 1I shows a similar configuration to FIG. 1H but also includes afeedback sensor that monitors the state of the nerve tissue and/orregion proximal to the nerve N.

FIG. 1J illustrates current vs. time and nerve block status vs. timecharts similar to FIG. 1I.

FIG. 2A shows a dual electrode system in which two EICCCs interface witha nerve, according to some embodiments.

As shown in the graphs of FIG. 2B, two electrodes are driven withcurrents of opposite polarities as a function of time such that when oneis in an active blocking phase, the other is in an inactive non-blockingphase which resets the electrode for blocking once the current polarityis again reversed.

FIGS. 3A-B show an embodiment where dual traditional electrodesinterface with a nerve but are driven from a current source viaelectrically insulated leads with currents of opposite polarities suchthat when one is in a blocking phase, the other is in a non-blockingphase which resets the electrode for blocking once the current polarityis again reversed.

FIGS. 3C-D show an embodiment where dual EICCCs interface with a nerve Nbut are driven with currents of opposite polarities such that when oneis in a blocking phase, the other is in a non-blocking phase whichresets the electrode for blocking once the current polarity is againreversed.

FIG. 4A shows an embodiment of an EICCC electrode in which an electrodeis immersed in an electrolyte solution which fluidly in is contact withan ion-conductive material such as a hydrogel, gel or other polymer thatelectrically contacts the nerve tissue or area proximal to the nervetissue.

FIG. 4B shows a system similar to that shown in FIG. 4A with theaddition of a reference electrode in proximity to the electrode (workingelectrode) to monitor voltage drop across the working electrode forEICCC monitoring purposes.

FIG. 4C shows a system similar to that shown in FIG. 4A with theaddition of a reference electrode in proximity to the nerve tissueinterface to monitor voltage drop across the EICCC to the nerve tissuefor EICCC monitoring purposes.

FIGS. 4D-4F show an embodiment of an electrode lead configured to pluginto and extend from a current source (not shown, near end) that mighttake the form of conventional IPGs (implantable pulse generators).

FIG. 4G shows a schematic embodiment of an EICCC integrated within ahermitically sealed enclosure which contains the current source, batteryor power supply, and controller to drive the EICCC.

FIGS. 5A-B show an embodiment of an electrode configuration in which twoelectrode contacts are housed within the same electrically insulatedenclosure.

FIG. 6A illustrates a dorsal root, and/or dorsal root ganglion (DRG)through which pain signals pass.

FIG. 6B shows an embodiment of a blocking electrode positioned along aDRG to facilitate nerve block along with lead and current source.

FIG. 6C illustrates that a DRG can be accessed with a needle, and theneedle can be used to penetrate the dura mater as shown.

As shown in FIG. 6D and FIG. 6E, the electrode-nerve interface contactscan then be positioned in contact or proximal to the DRG and theintroducing needle can be retracted to leave the electrode lead andnerve tissue interface in the desired position.

FIG. 7 shows associated dorsal root ganglia from each vertebral levelcorrespond to specific dermatomes in the body, and blocking pain signalsat the DRG level can reduce pain sensation at the innervated dermatomefor that specific DRG.

FIG. 8A illustrates placement of stimulating electrodes in proximity tothe lateral spinothalamic tract (LT tract), which can leverage an EICCCto generate a nerve block at the desired level (and/or spinal levelsdistal (away from the head) to the EICCC since pain signals travel inthe superior direction) and provide selective pain block depending onunilateral (left or right) or bilateral placement of electrodes.

FIG. 8B illustrates a percutaneous placement procedure with or withoutfluoroscopic guidance such as by using a Tuohy or similar needle tointroduce the electrode lead into the epidural space.

The leads can be directed along the spinal column within the epiduralspace such that the lead is between spinal nerve exit regions and thetissue interface is in proximity to the lateral spinothalamic tract asillustrated in FIGS. 8C-8E.

FIG. 9A shows an electron-ion current conversion cell (EICCC) electrodeconfigured to interface with a deep brain block (DBB) target in thethalamus.

In FIG. 9B an embodiment of a blocking/suppressing electrode with anintegrated sensing electrode is shown.

An embodiment of an EICCC electrode is shown in FIGS. 10A-10C in whichmultiple tissue interfaces are present on the electrode and areindividually addressable.

FIG. 10B is a close-up view of 10B-10B of FIG. 10A.

FIG. 10C is a close-up view of 10C-10C of FIG. 10A.

As shown in FIG. 11 , the blocking electrode leads contact the renalnerves to facilitate a block or suppression Also systematicallyillustrated is EICCC openly connected at to current source (not shown).

As shown in FIG. 12 , the relevant sympathetic ganglia including thecervical and stellate (cervicothoracic) ganglia are shown along withtheir innervation targets in the heart.

FIG. 13 illustrates select sympathetic nervous system-related anatomy.

FIG. 14 illustrates an embodiment of an EICCC electrode placed around orin proximity to the right (and/or left) vagus nerve within the rightside of the neck and/or chest with an electrode lead running down towardan implantable current source shown in the right pectoral region.

FIGS. 15-16 illustrate an embodiment of a dual EICCC system in whicheach vagus nerve is wrapped in a cuff-format tissue interface at whichionic current is deposited at the tissue site from the EICCCs.

FIG. 17 schematically illustrates non-limiting anatomy where sympatheticnerve suppression or block can also be used to regulate hepatic functionand influence glucose and insulin production.

FIG. 18 illustrates an EICCC system in which the nerves around thehepatic artery and the artery are surrounded by a cuff-format tissueinterface, according to some embodiments of the invention.

FIG. 19 illustrates a driving voltage waveform and positive and negativethresholds over a period of time.

FIG. 20 illustrates a driving voltage waveform, and positive andnegative thresholds over a period of time.

FIG. 21 illustrates schematically a voltage and current versus timegraph illustrating an electrode annealing process in which the currentamplitude is being ramped to a set target while the driving voltage isheld below a set threshold.

FIG. 22 illustrates a system that can include a nerve-tissue interfaceoperably connected to a catheter configured to hold a liquid.

FIG. 23A illustrates a system including a reaction chamber including areaction material.

FIG. 23B illustrates a separated interface nerve electrode that caninclude an integrated sensor for detecting the electrochemical status ofa reaction/working electrode.

FIG. 24 illustrates that systems and methods can utilize battery-typechemistries to deliver DC current to tissue, such as lead-acid battery,nickel-cadmium, nickel metal hydride, lithium ion, lithium polymer,zinc-carbon, biobatteries, or other types of battery chemistries.

FIG. 24 illustrates that systems and methods can utilize battery-typechemistries to deliver DC current to tissue.

FIG. 25 illustrates schematically a SINE-type electrode modified toallow for attachment at the site of the patient to reduce the length andthe impedance of the catheter.

FIG. 26A illustrates a wearable system including a DC generator, wire,and reaction chamber, with a portion of the lead/catheter implanted atthe desired anatomical site. FIG. 26B illustrates a bandage-style systemthat is local to the site of treatment (e.g., nerve block). FIG. 26Cshows a schematic embodiment of such a wearable device with twodifferent lead exit configurations.

FIGS. 27A-27D disclose methods of treating pain or other conditions bycycling DC block at a plurality of locations spaced apart from eachother.

FIG. 28A schematically illustrates a DC current system including anoptional reference electrode for voltage monitoring. In the simpleexample shown in FIG. 28B, electrode voltage increases with continued DCcurrent delivery.

FIG. 29 illustrates that voltage can be kept within a desired range withupper and lower threshold bands, which limits the electrochemistryoccurring at the electrode site

FIGS. 30A-30C Also disclosed herein in some embodiments are single-faultsafe DC systems and methods.

FIG. 31 schematically illustrates a silver-silver chloride electrode.

FIG. 32 illustrates a counterelectrode and working electrode are shownimmersed in an electrolyte bath and connected to a power supply whichdrives a potential across the two electrodes.

FIG. 33 illustrates driving voltages on a working electrode.

FIG. 34 illustrates that cycling of the silver/silver-chloride reactionat fixed current amplitude and fixed durations has been demonstrated tolead to decreases in peak driving voltages with increasing number ofcycles.

FIG. 35 illustrates that a working electrode and counterelectrodeformation are processed in the formation step where the current levelstarts at a relatively low value and rises with each cycle when thedriving voltage upper threshold is not exceeded.

FIG. 36 shows the change in microstructure that can occur after buildingan AgCl layer on a bare silver electrode and after performing theformation and stabilization steps to condition the AgCl-coatedelectrode.

FIG. 37 shows a driving voltage which started to exceed the drivingvoltage lower threshold over time.

FIG. 38 illustrates that the electrode and body can be modeled as aresistor (R_(lead)) and capacitor (C_(lead)) in parallel and a bodyimpedance (R_(body)) in series with the electrode. At low drivingfrequencies, the electrode and body can be modeled as shown in FIG. 39reflective of the equation above. At high driving frequencies the systemcan be modeled as shown in FIG. 40 where the capacitor behaves like ashort and does not have any impedance.

FIG. 41 illustrates a portion of a waveform where the threshold isreached, the current is reduced to stay below the threshold.

FIGS. 42A-C show schematically an embodiment of an electrode leadconfigured to deliver ionic direct current to tissue in proximity to thelead.

FIGS. 43A-43D show an embodiment of an electrode lead configured todeliver ionic direct current to tissue in proximity to the lead.

FIGS. 44A-44C illustrate another embodiment of an electrode lead whereinthe ionically conductive medium in FIG. 43A-43D is absent, and insteadthe ionically selective membrane is in direct contact with the ioniccurrent generator and insulator exterior surface.

FIGS. 45A-45C show an embodiment of an electrode lead configured todeliver ionic direct current to tissue in proximity to the lead.

FIG. 46 shows an alternative embodiment to FIGS. 45A-45C in which anelectrode lead comprises a portion through which ionic current can passinto the tissue, and an electrically insulated portion.

FIG. 47 shows an embodiment of an electrode lead including multiplespaced-apart ionically conductive portions.

FIG. 48 shows that in a rat model, a stimulation force of thegastrocnemius muscle due to stimulation of the sciatic nerve can betuned such that the nerve is unblocked (0%) or fully blocked (100%) ortuned to a partial block between 0% and 100%.

FIG. 49 shows an embodiment of a multi-contact electrode lead configuredto deliver ionic direct current to tissue in proximity to the lead.

FIGS. 50A-50B illustrate an alternate configuration of a curvedmulti-contact electrode lead configured to deliver ionic direct currentto tissue in proximity to the lead.

FIG. 51 illustrates that the ionic current generation portion 3 of theelectrode may be generalized to having a conversion mechanism fromelectrical current supplied by the electrical connection to anelectrochemical system which convert the electrical current into ioniccurrent.

FIG. 52 illustrates how an ionically conductive portion of the electrodecan be configured to generate a more even current density profile alongthe width of the electrode.

FIGS. 53A-53D illustrates one embodiment of an ionic direct currentelectrode lead with paired ionic current generation contacts that can beadhered using a helical wire form.

FIGS. 54A and 54B illustrate a lead sub-assembly and a lead with one ora plurality of contacts as previously described in connection with FIGS.53A-53D above.

FIGS. 55A-55D illustrate further views of electrode leads.

FIGS. 56A-56C schematically illustrate a generally tubular, e.g.,cylindrical lead contact that can include a sidewall with distal notchesand an interior lumen.

FIGS. 57A-57C schematically illustrate additional lead embodiments,illustrating conduits and spaced-apart lead contacts as previouslydescribed.

FIGS. 58A-58D illustrates embodiments of lead electrodes having paddleconfigurations.

FIG. 59 illustrates an embodiment of a cylindrical lead

FIGS. 60-62 illustrate various clinical treatment flowchart algorithmsincluding direct current therapy.

FIG. 63 illustrates an embodiment of an electrode lead system operatedin continuous block mode.

FIGS. 64A-64H illustrate various embodiments of separated interfacenerve (SINE) electrodes.

FIGS. 65A-65C illustrate embodiments of high charge density electrodesand electrode leads.

FIGS. 65D-65E illustrate embodiments of a surface area multiplicationtechnology technique that can include texturing of a rod and/or tube.FIG. 65F illustrates an embodiment of a surface area multiplicationtechnology technique that can involve laser texturing of a titaniumfoil/sheet.

FIGS. 65G-65K illustrate that the cathodic charge storage capacity(shaded regions) can be measured using cyclic voltammetry.

FIGS. 66A-66C schematically illustrate embodiments of various aspects ofmedical electrical delivery systems and components.

FIGS. 67A-67C illustrate examples of a pulse generator waveform that canadvantageously assist in achieving full nerve block quickly withoutunwanted side effects.

DETAILED DESCRIPTION

This application describes, in some aspects, methods and systems formanagement of chronic and acute pain states via safe application ofdirect current (DC) to facilitate nerve block including nervehypersuppression, or nerve block without rapid reversibility or recoveryafter direct current application has been removed or stopped. Byinterfacing with the nerve via ionic conduction pathways instead ofconventional electrodes that that do not have an ionic conductioncomponent, an intermittent or continuous short term and long-term nerveblock can be generated while reducing risk of damage to the nerve cells.What is disclosed in some embodiments are systems and electrodes forsafely delivering blocking direct current (DC) to neural tissue bydelivering cycled cathodic and anodic current through a high-chargechemistry. Tissue safety can be maintained by separating the metalinterface from the nerve tissue with an ionically conductive element,and by operating the electrode below reaction potentials for undesiredreactions, such as electrolysis of water, or oxidation and reduction ofwater (H2O), which create harmful reactive species such as OH—, H+ oroxygen free radicals.

Not to be limited by theory, the propagation of action potentials inelectrically excitable tissue, e.g. neural tissue, leads to refractoryperiods on the order of milliseconds for sodium channels, typicallybetween about 1 ms and about 20 ms, or between about 2 ms and about 5 msfor the combined absolute and relative refractory periods, thus very lowfrequency AC current waveforms with half periods meaningfully greaterthan this refractory period (e.g., greater than about 1 ms, 1.5 ms, 2ms, 2.5 ms, 3 ms, or more) can also be used to create tissue blockade,and will be perceived by electrically excitable tissue as a directcurrent stimulus. As such, direct current as defined herein is inclusiveof low frequency AC current waveforms that are perceived as andfunctionally is direct current from the perspective of the tissue whoseaction potentials are being modulated. The frequency could be, forexample, less than about 1 Hz, 0.5 Hz, 0.1 Hz, 0.05 Hz, 0.01 Hz, 0.005Hz, 0.0001 Hz, or ranges including any two of the foregoing values solong as the direction of current flow is constant over at least theentire refractory period of the target tissue, or at least twice as longas the refractory-causing membrane channel time constant (for example,fast sodium channel inactivation gate time constant)

Chronic pain is a significant burden on individuals and society as awhole. Nearly 50 million adults are estimated to have significantchronic or severe pain in the US alone. (See Nahin, Estimates of PainPrevalence and Severity in Adults: United States, 2012, The Journal ofPain, 2015 Aug. 16(8): 769-780) Worldwide, chronic pain is estimated toaffect more than 1.5 billion people. (Borsook, A Future Without ChronicPain: Neuroscience and Clinical Research, Cerebrum, 2012 June) Whilesurgical techniques are sometimes applied to remove a specific source ofpain, typically due to impingement of a nerve, in many cases the precisecause of pain is not clear and cannot be reliably addressed via asurgical procedure. Pain management can alternatively be addressed byoverwhelming the central nervous system with stimulating signals thatprevent registration of pain inputs (gate control theory of pain).Typically, this stimulation in the case of spinal cord stimulation (SCS)is performed using metal electrodes and alternating current (AC)stimulation to produce these additional stimulating signals to preventpain sensation. However, one major drawback is the presence ofparesthesia, a sensation of tingling in the innervated region downstreamfrom the stimulated nerve. Methods to eliminate paresthesia whichpatients can find discomforting have led to different means ofstimulation from conventional tonic SCS (˜30-120 Hz) stimulationincluding high frequency stimulation (˜10 kHz) and burst stimulation(e.g., five pulses at 500 Hz delivered 40 times per second).(Tjepkema-Cloostermans et al, Effect of Burst Evaluated in PatientsFamiliar With Spinal Cord Stimulation, Neuromodulation, 2016 Jul.19(5):492-497).

An alternative means to manage pain signaling to the central nervoussystem is to prevent conduction of the pain signals from the peripheralsignal source by directly blocking the pain signals as compared tomasking the pain signals by generating alternative neural inputs tocrowd out and inhibit pain signal transmission as in traditional SCS andgate theory. One means to do this is by applying a direct current (DC)to a nerve to prevent action potential (AP) generation and transmission.Because this does not stimulate the nerve as in traditional stimulation,paresthesia can be avoided. The mechanism leading to AP block has beenattributed to a depolarization block that deactivates the sodiumchannels required for an action potential event under the electrodesite. (See Bhadra and Kilgore, Direct Current Electrical ConductionBlock of Peripheral Nerve, IEEE Transactions on Neural Systems andRehabilitation Engineering, 2004 Sep. 12(3): 313-324).

Bhadra et al. showed that upon application of DC to nerve tissue, actionpotential conduction can be blocked (See Bhadra and Kilgore, DirectCurrent Electrical Conduction Block of Peripheral Nerve, IEEETransactions on Neural Systems and Rehabilitation Engineering, 2004 Sep.12(3): 313-324). The authors showed that removal of DC delivery from thesame nerve tissue resulted in instantaneous restoration of nerveconduction. However, direct current has long been known to be dangerousto nerve tissue due to creation of toxic species at the electrode-nerveinterface (Merrill, Electrical Stimulation of Excitable Tissue: Designof Efficacious and Safe Protocols, Journal of Neuroscience Methods,2005, 141:171-198). Ackermann et al and Fridman et al have developedsystems and methods of safely delivering DC to nerve tissue byseparating the toxic species created at the electrode interface from thenerve tissue (U.S. Pat. Nos. 9,008,800 and 9,498,621; Ackermann et al,Separated Interface Nerve Electrode Prevents Direct Current InducedNerve Damage, J Neurosci Methods, 2011 Sep. 201(1):173-176; Fridman andSantina, Safe Direct Current Stimulation to Expand Capabilities ofNeural Prostheses, IEEE Transaction of Neural Systems and RehabilitationEngineering, 2013 Mar. 21(2):319-328; Fridman and Santina, Safe DirectCurrent Stimulator 2: Concept and Design, Conf Proc IEEE Eng Med BioSoc, 2013: 3126-3129), each of the foregoing of which are incorporatedby reference in their entireties. They also teach that rapidreversibility of nerve blockade is desirable and achievable throughhalting of DC delivery. Ackermann et al. teaches that an undesired, butreversible, suppression of nerve activity occurs with long term directcurrent delivery (where nerve tissue was shown to be non-conductive fora short period of time following cessation of DC delivery) (U.S. Pat.Nos. 9,008,800 and 9,498,621; Ackermann et al, Separated Interface NerveElectrode Prevents Direct Current Induced Nerve Damage, J NeurosciMethods, 2011 September 201(1):173-176), each of which are incorporatedby reference in their entireties. Those authors specifically teachmethods to reduce this suppression of nerve activity by limiting theduration of DC delivery to allow rapid nerve recovery upon cessation ofDC delivery (e.g., within seconds) (U.S. Pat. Nos. 9,008,800 and9,498,621; Ackermann et al, Separated Interface Nerve Electrode PreventsDirect Current Induced Nerve Damage, J Neurosci Methods, 2011 September201(1):173-176). What is invented and described herein in someembodiments are systems and methods for doing the opposite of that whichis taught by Ackermann et al: intentionally blocking nerve activity byusing periodic DC pulses to intentionally place neural tissue in a stateof hypersuppression without rapid reversibility upon cessation of DCdelivery (reversibility that occurs in many minutes to hours, as opposedto seconds or less than a minute). Furthermore, what is invented anddescribed herein in some embodiments are systems and methods of treatingpain by the aforementioned systems and methods, specifically throughselective blockade of antero-lateral column tissue in the spinal cord.Furthermore, what is invented and described herein are systems andmethods of treating pain by the aforementioned systems and methods,specifically through selective blockade of dorsal root tissue and/ordorsal root ganglia. Furthermore, what is invented and described hereinare systems and methods of treating pain by the aforementioned systemsand methods, specifically through blockade of one or more peripheralnerves.

With targeted nerve block, pain from specific dermatomes and pain inregional body sites can be managed. A number of localized targetsimplicated in moderating pain signal transduction can be addressed. Forexample, both more centrally located nerve tissues such as thespinothalamic tract and dorsal root ganglion can be targeted to managelower back pain, sciatica, and complex regional pain syndrome (CPRS)among other pain considerations.

Electrodes where current in the form of ions is generated proximal tothe at least one target nerve may comprise an ionically conductivematerial such as a liquid (e.g., saline or other electrolyte solution),gel, hydrogel, hydrocolloid, polymer, or film. In an alternativeembodiment, the ionically conductive materials may be separated by ascreen or other filter or membrane material from the nerve tissue. Thisseparating interface may be configured to selectively allow ions throughto the nerve to reduce nerve damage such as microporous screens,non-woven screens, ion-exchange membranes (IEM), supported liquidmembranes or ionogels, polymer electrolytes such as polyethylene oxide(PEO), polypropylene oxide (PPO), polyvinylidenefluoride-co-hexafluoropropylene copolymer (PVDF-HFP), solid ionconductors, and ion-selective films including cation exchange membranesand anion exchange membranes.

The nerve-interfacing element of the electrode may be further configuredto be exposed selectively along the electrode and may be otherwiseinsulated from the nerve by an ionically impermeable layer. Theimpermeable layer may also be configured to be electrically insulatingto current.

The ionically conducting material may also be separated into multipleregions which may contain different types of ionically conductingmaterial. The interfaces between the different regions may be delineatedby semi-permeable membranes or screens that allow for selective orgeneral ionic flow but limit the passage of damaging by products fromthe conversion of electron current to ionic current. This separatingelement may be configured to selectively allow ions through to the nerveto reduce nerve damage such as microporous screens, non-woven screens,ion-exchange membranes (IEM), supported liquid membranes or ionogels,polymer electrolytes such as polyethylene oxide (PEO), polypropyleneoxide (PPO), polyvinylidene fluoride-co-hexafluoropropylene copolymer(PVDF-HFP), solid ion conductors, and ion-selective films includingcation exchange membranes and anion exchange membranes. The differentionically conducting materials may also take different forms. As anexample, the nerve may be in contact with a hydrogel which is in contactwith a liquid such as an electrolyte solution which then is in contactwith a traditional electrical current electrode material.

In some embodiments the traditional electrode may be made from amaterial such as platinum, platinum-iridium, carbon, titanium nitride,copper, tantalum, silver, silver-chloride or other metals and materialsor combinations thereof. In some embodiments, the traditional electrodemay be made from carbon, graphite, glassy carbon, dendritic carbon, orother conductive materials. By using high-charge chemistry amplitude andduration of direct current (DC) block can be increased. Candidatechemistries include using a combination of Ag/AgCl electrode in anelectrolyte bath (or other suitable ionically conductive material) suchas saline that is in ionic contact with neural tissue of interest. Insome embodiments the electrode is reversible and can be restored to itsinitial state. In some embodiments the electrode is sacrificial and theelectrochemical reaction that occurs at the electrode cannot be reversedto restore the electrode to its initial state.

Electrodes can be made of a variety of materials. In some embodiments,electrode can be made of silver (Ag) and/or silver chloride (AgCl). Insome embodiments, electrode can be made of titanium nitride (TiN). Insome embodiments, electrode can be made of carbon (C). In someembodiments, the electrode has an ion-selective coating or membrane. Insome embodiments, the electrode does not have an ion-selective coatingor membrane.

In some embodiments, an electrode can include a contact comprising ahigh charge-capacity material. The electrode contact can have in somecases a geometric surface area of between about 1 mm² and about 10 mm²,or about 1 mm², 2 mm², 3 mm², 4 mm², 5 mm², 6 mm², 7 mm², 8 mm², 9 mm²,10 mm², 20 mm², 50 mm², 100 mm², or ranges including any two of theforegoing values. The electrode contact itself can be fabricated of ahigh charge capacity material, such as those described, for example, inU.S. Pat. No. 10,071,241 to Bhadra et al., which is hereby incorporatedby reference in its entirety. Alternatively, the electrode contact cancomprise a base at least partially, or entirely coated with a highcharge capacity material. In some embodiments, a high charge capacitymaterial can have a Q value of at least about 25, 50, 100, 200, 300,400, 500, 1,000, 2,500, 5,000, 10,000, 50,000, 1000,000, 500,000, ormore μC, or ranges including any two of the foregoing values. The Qvalue of an electrode contact can refer to the total amount of chargethat can be delivered through an electrode contact before the electrodecontact begins having irreversible chemical reactions, such as oxygen orhydrogen evolution, or dissolution of the electrode materials.Non-limiting examples of high charge capacity materials are platinumblack, iridium oxide, titanium nitride, tantalum, silver chloride,poly(ethylenedioxythiophene) and suitable combinations thereof. Theelectrodes could be fractal coated electrodes in some embodiments. Togenerate more surface area for the electrochemical reactions to occur,the traditional electrodes may be made from high surface area to volumestructures such as roughened surfaces, woven surfaces, patternedsurfaces, reticulated foam structures, porous sintered bead structures,nano- or micro-patterned structures to expose additional materialsurface area. In some embodiments, the electrode can be a SINE(separated-interface nerve electrode) or EICCC (electron to ion currentconversion cell) electrode in which an electrode is immersed in anelectrolyte solution which is in contact with an ion-conductivematerial-electrolyte solution interface with an ion-conductive materialthat electrically contacts the cardiac tissue or area proximal tocardiac tissue, as described, for example, in U.S. Pat. No. 9,008,800 toAckermann et al., and U.S. Pub. No. 2018/0280691 to Ackermann et al.,which is hereby incorporated by reference in their entireties.

The combination of traditional electron-carrying electrode material andionic conducting material and the conversion mechanism can becollectively characterized as an electron-ion current conversion cell(EICCC). One such example might be a silver/silver chloride (Ag/AgCl)electrode immersed in a saline, e.g., isotonic 0.9% NaCl saline solutionfluidly in contact with a saline-containing hydrogel. Upon driving of anelectric current through the conventional electrode, reduction of thesolid AgCl will drive conversion to solid Ag and Cl— ion formationgenerating a flow of ions or an ion current. This ionic current flow canbe used to modulate the nerve membrane potential and, for example,create a blockade of nerve conduction. The membrane potential may bemodulated in such a manner that the potential is ramped up slowly enoughto avoid action potential generation as the nerve tissue is depolarized.Upon reversal of the electric current, oxidation of the previouslyformed Ag or other Ag in the Ag/AgCl electrode will be oxidized togenerate AgCl deposits on the electrode, driving the ion current in theopposite direction. Due to the extremely low solubility of Ag and AgClin saline, the electrode remains mechanically intact during forward andreverse current delivery. In combination, the reduction-oxidationreactions create a fully reversible EICCC. To maintain the preferredreduction-oxidation reaction between Ag and AgCl (or other electrodematerials), the amount, e.g., mass, volume, density, or anotherparameter of the AgCl on the electrode may be maintained within 5%-95%,10%-90%, 20%-80%, 25%-75%, 30%-70% of its original starting mass on theelectrode to ensure that the AgCl is never depleted or saturated,enabling other deleterious reactions from happening at the electrode. Insome embodiments, the amount of the electrode can be maintained at leastabout, or no more than about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or ranges ofbetween about any two of the foregoing values. In other words, theelectrode is reversible and can be restored to its original orsubstantially to its near-original state. To generate more surface areafor the electrochemical reactions to occur, the traditional electrodesmay be made from high surface area to volume structures such asroughened surfaces, woven surfaces, patterned surfaces, reticulated foamstructures, porous sintered bead structures, nano- or micro-patternedstructures to expose additional material surface area. High-chargechemistry electrodes can be biocompatible, or suitably sequestered frombody if not. A high surface area electrode material (e.g. Ag/AgCl) inthe EICCC may be utilized specifically to decrease the electrodepotential drop or to reduce the increase in electrode potential dropwhich may occur with prolonged current delivery. In some embodiments theEICCC driving current may be between about 0 mA and about 1 mA, betweenabout 1 mA and about 2 mA, between about 2 mA and about 4 mA, betweenabout 4 mA and about 8 mA, higher than about 8 mA, about 0.5 mA, 1 mA, 2mA, 3 mA, 4 mA, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA, 10 mA, or rangesincorporating any two of the foregoing values. In some embodiments thisdriving current is then used to generate a corresponding ionic currentof similar magnitude, depending on the specific electrochemicalreactions.

Another embodiment of the EICCC may comprise a material such as tantalumor titanium nitride to generate a capacitive traditional electrodeinterface instead of an interface at which an electrochemical reactionoccurs. Transparent conducting oxides (TCOs) such as fluorine-doped tinoxide (FTO), nickel titanium dioxide (Ni/TiO2), and other titaniumdioxide (TiO2) constructs are also candidate materials that have highcharge carrying capacities. In this configuration, charge generation atthe traditional electrode surface would attract ionic species from theionically conductive material until the charge at the traditionalelectrode interface is passivated. Charging of the capacitive materialwith an electric current of one polarity can generate current flow inthe form of ions. Reversing the polarity of the current flow to thecapacitive material can effectively reset the system for a subsequentcharging to generate further ionic current flow. To generate moresurface area for increased ion current flow capacity to occur, thetraditional electrodes may be made from high surface area to volumestructures such as roughened surfaces, reticulated foam structures,porous sintered bead structures, nano- or micro-patterned structures toexpose additional material surface area. In one embodiment, thiscapacitive structure is in fluid contact with an electrolyte solutionthat contacts an electrolyte-saturated hydrogel in contact with targetnerve tissue to enable ion current flow to the tissue. In someembodiments, the solution is body fluid such as interstitial fluid thatdelivers the current to the electrically excitable tissue from theelectrode.

In a further embodiment of the EICCC, a combination of bothelectrochemical and capacitive mechanisms may be used to convert currentin the form of electrons to current in the form of ions.

To deliver ionic current to the nerve to facilitate a block, thetraditional electrode may be connected via a conductive lead to one ormore current sources. A single nerve-electrode interface can providenerve block when current is applied in one polarity to the EICCC(blocking phase). When the current polarity is reversed to return theelectrode to its original state (which may be a non-blocking phase oralso a blocking phase), the nerve may or may not continue to block painstimulus from passing along the nerve. If the nerve has been placed intoa state of hypersuppression, the nerve will continue to prevent APpropagation and block pain regardless of the phase state of theelectrode. Fridman and Santina have described a means to enablecontinuous block when current polarity is reversed as driven by analternating current (AC) using a series of valves to direct current flowdirection (Fridman and Santina, Safe Direct Current Stimulation toExpand Capabilities of Neural Prostheses, IEEE Transaction of NeuralSystems and Rehabilitation Engineering, 2013 Mar. 21(2):319-328; Fridmanand Santina, Safe Direct Current Stimulator 2: Concept and Design, ConfProc IEEE Eng Med Bio Soc, 2013: 3126-3129). However, in some cases itis desirable to have a more simple system which does not require the useof valves which present additional failure points and add bulk to animplantable system. A simpler, more robust system may be configuredwithout valves and such moving parts by using multiple EICCCs to provideconstant stimulation of the nerve tissue itself. In one embodiment toprovide continuous block, two nerve-electrode interfaces are present andconnected to one or more current sources. The first nerve-electrodeinterface EICCC is run with the current in one polarity to drive a blockwhile the second nerve-electrode interface EICCC is run with theopposite polarity. After a period of time, the current polarities of thefirst and second EICCCs are reversed and the second nerve-electrodeinterface provides a block while the first nerve-electrode interfaceEICCC state is reversed to its prior state. By cycling the dual-EICCCelectrode currents, a continuous block can be maintained at the targetnerve. As can be appreciated, more than two, such as 3, 4, 5, 6, 7, 8,9, 10, or more EICCCs may also be used to facilitate the same continuousblock. Electrodes may also be run in either monopolar or bipolarconfigurations. In some embodiments the EICCC system is configured tonot have any mechanically moving parts such as valves or hinges.

Alternatively, nerve activity may be suppressed which means that nerveactivity remains blocked even after removal or discontinuation of theblocking current. The nerve may be further put into a state ofhypersuppression in which the nerve remains blocked without rapidreversibility after cessation of DC delivery. Modulation of the initialcurrent delivered to the nerve tissue including ramp rate, currentamplitude, total charge delivery, and waveform shape can be used toplace the nerve in a state of suppression. During the state ofsuppression, the EICCC may be returned to its initial state by reversingthe current polarity used to generate the initial block and suppressionstate. During the period of reverse current flow, the nerve may remainin a state of hypersuppression. In another configuration the EICCC maydeliver subsequent blocking current inputs that extend the suppressionduration, with periods of no current delivery, or of reversal current inbetween blocking current doses. The nerve tissue may remain in a stateof hypersuppression during the periods of non-blocking current input. Inanother configuration, the EICCC may be configured to deliver subsequentcurrent inputs on a schedule. In some embodiments, the DC block waveformmay have an amplitude of between 0-250 microamps, 250-500 microamps,500-1000 microamps, 1000-1500 microamps, or 2000 microamps, or higher,or about, at least about, or no more than about 50, 100, 150, 200, 300,400, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500,1,600, 1,700, 1800, 1,900, 2000 microamps or more, or other rangesincorporating any two of the aforementioned values. Placing a nerve intoa state of hypersuppression may be facilitated in some embodiments bydelivering a charge of 10-50 millicoulombs, 50-100 millicoulombs,100-500 millicoulombs, 500-1000 millicoulombs, or 1000 millicoulombs orgreater, or about, at least about, or no more than about 10, 25, 50,100, 200, 300, 400, 500, 600, 700, 800, 900, 1,000, or moremillicoulombs, or other ranges incorporating any two of theaforementioned values, and depending on nerve size and desiredhypersuppression duration. DC block amplitude and current duration maybe tuned to enable hypersuppression in the range of, for example, 0-0.5times the duration of initial DC block, 0.5-1 times the duration ofinitial DC block, 1-1.5 times the duration of initial DC block, 1.5-2times the duration of initial DC block, and greater than 2 times theduration of initial DC block, or about, at least about, or no more thanabout 0.1×, 0.2×, 0.3×, 0.4×, 0.5×, 0.6×, 0.7×, 0.8×, 0.9×, 1×, 1.1×,1.2×, 1.3×, 1.4×, 1.5×, 1.6×, 1.7×, 1.8×, 1.9×, 2×, 2.5×, 3×, 4×, 5×, ormore relative to the duration of initial DC block, or ranges includingany two of the aforementioned values.

Sensing the local state of and proximal to the nerve tissue can alsoprovide a useful measure for determining when to provide current inputsto extend nerve suppression as well as to provide a feedback loop forinitial current delivery to generate the initial nerve block bymodulating the nerve potential such that it cannot transmit actionpotentials. In one embodiment the nerve's ability to conduct actionpotentials is monitored such that as direct current is delivered to thenerve tissue, the direct current delivery can be maintained to ensurethat the nerve block is maintained, for example. Nerve conductionability may be monitored by any suitable measure such as delivering astimulus pulse and measuring compound action potential signal.

In some embodiments sensing is in the form of a reference electrode tomeasure potential differences relative to the two electrodes which arepassing the active current. In some embodiments the active current ismodulated in response to one or more measured electrode potentialsrelative to the reference electrode. In some embodiments the activecurrent is modulated when measured electrode potential indicates thatundesired electrochemical reactions may occur at one or more activeelectrodes. For example, active current may be reduced or ceased uponmeasurement of an active electrode potential that indicates waterelectrolysis is occurring or possible. The EICCC may be operated with adirect current input or by applying a potential difference between theworking electrode and an auxiliary or counter electrode. In someembodiments, a reference electrode may be located within the EICCC or atthe distal end of the EICCC proximal to the nerve tissue.

FIG. 1A shows an embodiment of an EICCC electrode 100 in which anelectrode 104 is immersed in an electrolyte solution 102 which in iscontact with an ion-conductive material—electrolyte solution interface107 with an ion-conductive material 106 such as a fluid, hydrogel, gelor other polymer that electrically contacts the nerve tissue N or areaproximal to the nerve tissue N. The EICCC electrode 100 also comprisesan electrically insulated, biocompatible enclosure 108 housing thetraditional electrode 104, electrolyte 102, and biocompatible ionconducting material 106 with an aperture (near 110) to enable electricalcontact with the nerve N or area proximal to the nerve tissue N. Thesystem further comprises a current delivery lead 112 between the currentsource 114 and the electrode 104. The current source 114 may be locatedexternal or internal to the body depending on the application need. Anexemplary non-limiting embodiment of the EICCC 100 comprises a silver,silver-chloride (Ag/AgCl) electrode in a 0.9% saline solution in fluidcontact with an electrolyte saturated hydrogel (agar preparation with0.9% saline).

With an Ag/AgCl electrode used to generate current via reduction of theAgCl on the electrode in a saline solution (NaCl), a sustainable andreversible electrochemical reaction can be achieved to convert currentin the form of electrons into current in the form of ions. As seen inRegion 1 of FIG. 1B, by pushing a constant current from the currentsource, the mass of the AgCl electrode will decrease from mass m2 tomass m1 during a cathodic current (reduction reaction) and then increaseas seen in Region 2 from mass m1 back to mass m2 with an anodic currentduring an oxidative reaction. Furthermore, it can be appreciated that bylimiting the maximum mass of the AgCl to m2 such that the mass ofunreacted Ag is greater than zero helps prevent the Ag/AgCl reactionfrom depleting available Ag for the electrochemical reaction andprovides a reserve safety factor in the event of excess current deliverysimilar to maintaining m1 above zero. In Region 3, the current polarityis again reversed to match that of Region 1. By not depleting the AgClmass to zero, the preferred reaction between conversion of solid AgCl tosolid Ag with generation of chlorine ions and vice-versa:AgCl(s)+e ⁻⇔Ag(s)+Cl⁻Because water electrolysis or hydrolysis happens at higher reductionpotential than AgCl, AgCl dissolution will be preferred preventingundesired reactions and generation of OH—, H+ or oxygen free radicals inthe EICCC. Further notable is that the absolute value of the areabetween the current amplitude and the x-axis (time) can be used todefine the total charge delivered (or removed) from the electrode toallow for determination or prediction and/or control of the electrodeAgCl mass. It will be appreciated that the current waveform shapes inthe different regions need not be perfect square waves but may includefinite slopes that ramp from zero amplitude to their final maximumamplitude as well as from their maximum waveform amplitude back to zerocurrent. Waveforms may also be non-linear in pattern and may varybetween regions. In a preferred embodiment, the total charge deliveredin Region 1 is equivalent to the total charge removed in Region 2. Inother words, the magnitude of the area below the current waveform inRegion 1 is the same as that of Region 2. Different regions may also bespaced apart in time by a period of zero current (not shown) in whichthe AgCl electrode mass is conserved while no current is beingdelivered. Not to be limited by theory, the silver-silver chloridesystem offers several potential benefits over other electrochemicalreactions. For example, the standard potential of the silver-silverchloride reaction is about 0.22 V, which is advantageously well belowthe voltage at which electrolysis occurs. Electrolysis can occur whenthe magnitude of potential or voltage used to drive a reaction exceedsabout 1.23 volts referenced against the standard hydrogen electrode.Electrolysis of water can be detected via one or more sensors, and ceaseor modulate (increase or decrease) current delivery and/or drivingvoltage if electrolysis is detected in some cases. The sensors can alsodetect in some cases whether the silver-silver chloride reaction isexclusively, substantially exclusively, or predominantly occurringrather than electrolysis, hydrolysis, or a redox water reaction, forexample. Furthermore, the amount of charge that can be delivered by sucha system is not limited by surface area reactions such as in the case ofplatinum electrodes which form a monolayer of platinum-hydride on theelectrode surface before the available platinum for reaction isexhausted leading to other potentially harmful products forming if thereaction is continued to be driven. In contrast, in an aqueousenvironment when silver-chloride is reduced it forms solid silver andreleases a chloride ion into solution and vice-versa. The reaction ineach direction is only limited by the quantity of reactant available sothe reaction is in effect limited by the total volume of reactantavailable compared to being limited to surface area. As such, thereaction can utilize an amount of reactant greater than that of theinitial, unreacted surface area of the electrode, such as about or atleast about 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%,250%, 300%, 500%, 1,000%, 5,000%, 10,000%, 25,000%, 50,000%, 100,000%,500,000%, 1,000,000%, 2,500,000%, 5,000,000%, 10,000,000%, 25,000,000%,50,000,000%, 100,000,000%, 250,000,000%, 500,000,000%, 1,000,000,000%,or more of the initial total, unreacted surface area of the electrode,or ranges including any two of the aforementioned values and dependingon the volume of silver utilized. Therefore, substantially more, and insome cases orders of magnitude more charge can be advantageouslydelivered to body tissue while remaining below the electrolysisthreshold. For example, a platinum or platinum-iridium electrode mightdeliver 5 microcoulombs per pulse in a 5 mA pulse for 1 millisecond.With embodiment as disclosed herein, it can be possible to achieve aboutor at least about 1,000×, 5,000×, 10,000×, 50,000×, 100,000×, or moretimes this charge using DC delivery in the form of a 5 mA pulse with 10second duration. This may be achieved, for example, by creating a 1micron coating of AgCl on an electrode of nominal geometry of 3.5 mmlength (or between about 1 mm and about 10 mm in length, between about 1mm and about 5 mm in length, or between about 3 mm and about 4 mm inlength) and 1.4 mm diameter (or between about 0.5 mm and about 5 mm indiameter, between about 0.5 mm and about 3 mm in diameter, or betweenabout 1 mm and about 2 mm in diameter) comparable to existing platinumelectrodes. One skilled in the art will appreciate that depending onconfiguration and reservoir of silver-chloride available, the amount ofcharge delivered can increase to 10,000×, 100,000×, 1,000,000×,10,000,000×, 100,000,000× or more, or ranges incorporating any two ofthe aforementioned values, compared to that achievable using aconventional platinum electrode. The silver-silver chloride complex canthus be uniquely situated for use in body environments because thereaction chemistry involves chloride ions which are one of the mostreadily available ions in and around body tissue.

FIG. 1C shows how current being delivered to the electrode cell (EICCC)(top) can be associated with charge delivered to the electrodecell-nerve interface (middle) to provide nerve block (bottom) whileenabling zero net charge transfer with long charge phases. In Phase 1,charge can be delivered to the electrode cell with a given polarity andconstant or variable ramp rate (R1) to then provide a constant orvariable current (C1) with subsequent constant or variable ramp (R2)back to zero current. Phase 1 may be, for example, of duration up to 1second, 1 minute, 1 hour, 1 day, 1 month, or 1 year, or longer. In someembodiments, Phase 1 average current is non-zero, but instantaneouscurrent may at times be zero. In some embodiments, Phase 1 is eithercathodic or anodic but not both. The initial phase, Phase 1, may befollowed by an interphase interval (Interval 1) between cathodic andanodic phases that is greater than or equal to zero seconds. Subsequentto this interval, a second current delivery phase (Phase 2) which may beof duration up to 1 second, 1 minute, 1 hour, 1 day, 1 month, or 1 year,or longer can be applied. This second phase is of opposite polarity toPhase 1 where average current is non-zero, but instantaneous current mayat times be zero. In Phase 2, charge can be delivered to the electrodecell with a given polarity and constant or variable ramp rate (R3) tothen provide a constant or variable current (C2) with subsequentconstant or variable ramp (R4) back to zero current. This Phase 2 maythen be followed by another interphase interval (Interval 2) that isgreater than or equal to zero seconds. The waveform in FIG. 1C may berepeated with identical or differing amplitude and duration parametersas a previous waveform whereby the waveform may be programmed oradjusted by a clinician and/or patient and/or caregiver and/or controlsystem. Adjustments may include adjusting the currents in Phase 1 andPhase 2 such that currents are ramped up and/or down as well asadjusting the durations of the phases t1-t0 and t3-t2, respectively.Interphase intervals can also be adjusted such that their durationst2-t1 and t4-t3 are lengthened or shortened. Any delivery or interphaseperiod could be, for example, at least about, about, or no more thanabout 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 55 seconds; 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 15, 30, 60, 120 minutes; 3, 4, 5, 6, 7, 8, 9, 10,12, 16, 18, or 24 hours; 2, 3, 4, 5, 6, 7, 14, 21, 28, 30, 45, 60, 75,90, or more days; 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24 or more months;or ranges including any two of the aforementioned values.

At the nerve interface the current delivered to the electrode cell cangenerate an increase in charge (positive or negative) delivered to thenerve interface as shown and may be linear as shown or generallyincreasing in a linear or non-linear fashion in Phase 1. The net chargedelivered remains roughly constant during the gap phase or Interval 1then returns to zero during Phase 2. Initially, the period of nerveblock (FIG. 1C bottom) is initiated somewhere during the beginning ofPhase 1 and nerve block will remain active (solid line) while charge isbeing delivered to the nerve interface. However, nerve suppression asdefined by continued nerve block after removal of current delivery tothe electrode cell may continue after current delivery to the nerve isstopped and may persist into the Interval 1 period (ii), extend intoPhase 2 (iii) independent of the opposite polarity current beingdelivered, or into Interval 2 (iv), or beyond (not pictured). Tuning ofthese parameters can lead to the placement of the nerve into a state ofhypersuppression as seen in FIG. 1C (ii), (iii), (iv) in which nervesuppression may occur for durations greater than one minute afterremoval of DC delivery.

In FIG. 1D waveform patterns delivered to an electrode cell tofacilitate nerve block are shown in which current delivered to theelectrode cell is shown along with corresponding nerve block periodsincluding hypersuppression regions in which nerve block occursregardless of current being delivered to the nerve tissue. The electrodecell system is designed such that the cathode and/or anode phase isdesigned to place the neural tissue in a state of not being conductive(or partially conductive) after the cessation of the current for periodslonger than one minute (hypersuppression) after current delivery. InFIG. 1D(i) an electron current has been delivered to the electrode cellto generate an ion current at the neural tissue facilitating a nerveblock. After this initial current delivery, the neural tissue thenenters a state of hypersuppression whereby in the absence of additionalcurrent delivery to the neural tissue, the nerve cannot conduct signalsor is not fully conductive. The neural tissue suppressed state may alsobe extended as shown in FIG. 1D(ii) in which a secondary current isdelivered to the neural tissue a period of time after the initialcurrent has been delivered where the delivery of the extension currentmay occur up to one minute after the initial current is delivered orafter periods of longer than one minute (hypersuppression). This patternof suppression extension may be repeated for a defined period of time orindefinitely with constant or variable length intervals between currentdelivery phases. To maintain the electrode cell in a charge neutralstate over repeated uses, current with opposite polarity may be appliedafter the initial nerve block current is applied and has placed thenerve into a state of hypersuppression (FIG. 1D(iii)). Subsequently,current of the original polarity can be applied to induce additionalhypersuppression extension as shown. In this manner the nerve tissue canbe repeatedly “dosed” with anodic and/or cathodic safe DC current tomaintain the neural tissue in a state of hypersuppression. Thehypersuppression duration is longer in duration than a cathodic and/oranodic delivery phase, allowing for complete net charge reversal duringhypersuppression. In these examples, the duration and/or amplitude ofthe cathode and/or anode phase(s) can be programmed to influence theduration and completeness of the nerve block after current delivery hasstopped.

FIG. 1E shows an embodiment of an electron-ion current conversion cell(EICCC) 100 which is connected via an electrically insulated lead 112 toa current source 114. The EICCC 100 comprises a traditional electrode(electrode) 104 material (e.g., metal, carbon, etc.) connected to anionically conductive material (ion conductor 106) which then interfaceswith the nerve tissue N, or tissue in proximity to nerve tissue. In someembodiments, the interface can be within about 3 cm, 2.5 cm, 2 cm, 1.5cm, 1 cm, 5 mm, 2 mm, 1 mm, 0.5 mm, 0.1 mm, or less in proximity tonerve tissue. One skilled in the art will appreciate that theconventional electrode 104 and ionically conductive material 106 may beattached in a multitude of ways such as shown abutting or in aninterlocking fashion and the like. The electrode 104 may be insertedwithin the ion conductor 106 or vice-versa. As shown in FIG. 1F, in oneconfiguration when the electron current is of one polarity as designatedby the positive axis, the nerve block is shown to be active and when thepolarity of the current is reversed as designated by the negative axis,the nerve block is shown to be inactive. It should be appreciated thatin the case in which the initial blocking current is applied to thenerve N in such a manner to induce a state of hypersuppression, thenerve may remain N blocked during the current reversal period. Duringthe current reversal period, the EICCC 100 is in a resetting phase inwhich the reaction used to generate the ion current is reversed to bringthe EICCC 100 components back towards their original state forsubsequent blocking current generation.

FIG. 1G shows a similar configuration to FIG. 1E but with sequestrationscreens 118, 120 that respectively separate the traditional electrode104 from the ion conductor 106 and the ion conductor 106 from the nerveN itself, or nerve adjacent tissue. One of ordinary skill in the artwill appreciate that one, two, or more or no screens may be used, or anycombination thereof. The screens 118, 120 are configured to selectivelyallow certain ions to transfer between the respective materials whilerestricting the movement of other ions whose movement is not desired,for example to maintain reaction species such as Cl— near the electrode.The screens 118, 120 may be comprised of an ionically selective membranesuch as an anion exchange membrane that only allows anions to passthrough it. FIG. 1H illustrates current vs. time and nerve block statusvs. time charts similar to FIG. 1F.

FIG. 1I shows a similar configuration to FIG. 1G but also includes afeedback sensor 122 that monitors the state of the nerve tissue N and/orregion proximal to the nerve N. In some embodiments a sensor 122 may belocated proximal or distal to the electrode-nerve interface in order toenable measurement of local compound action potential to providefeedback to the current source 114 and EICCC 210 to enable it tomodulate electrode current and nerve interface electrode potential tomaintain hypersuppression. In some embodiments the sensor 122 maymeasure nerve tissue voltage signals and use that information asfeedback to modulate the current and electric potential generated at thenerve interface. In some embodiments the electric potential is modulatedsuch that the nerve cells are maintained in a depolarization state inwhich action potentials cannot propagate along the nerve cells. In someembodiments the sensor 122 comprises a reference electrode whereby thepotential difference between one or more working electrodes 104 and thereference electrode can be monitored and used as feedback to the currentsource 114 to ensure proper operating range of the EICCC 210. Theimplantable packaging may contain an integrated reference or counterelectrode. FIG. 1J illustrates current vs. time and nerve block statusvs. time charts similar to FIG. 1H.

FIG. 2A shows a dual electrode system in which two EICCCs 220A, 220Binterface with a nerve N or nerve adjacent tissue. The two electrodes220A, 220B are driven with currents of opposite polarities as a functionof time such that when one is in an active blocking phase, the other isin an inactive non-blocking phase which resets the electrode forblocking once the current polarity is again reversed as shown in FIG.2B. With this configuration a constant block can be maintained along thenerve N. It should be appreciated that in the case in which a blockingcurrent is applied to the nerve N in such a manner to induce a state ofhypersuppression, the nerve block may remain active during the currentreversal period of the electrodes 220A, 220B. One skilled in the artwill appreciate that the driving currents for the two electrodes 220A,220B may be spaced apart in time during which no current is driving oneor both electrodes 220A, 220B and that during this period block may bemaintained if the nerve N is in a state of suppression. Similarly, thedriving currents may be of different durations dependent on theelectrodes 220A, 220B themselves and any recovery time of the nerve Nduring which signal remains blocked while no blocking current is beingapplied. The electrodes 220A, 220B may be oriented as shown in seriesaxially along a nerve N or oriented on opposite sides to the nervetissue itself.

FIGS. 3A-B show an embodiment where dual traditional electrodes 104A,104B interface with a nerve N but are driven from a current source viaelectrically insulated leads 112 with currents of opposite polaritiessuch that when one is in a blocking phase, the other is in anon-blocking phase which resets the electrode for blocking once thecurrent polarity is again reversed. With this configuration a constantblock can be maintained along the nerve. The electrodes 104A, 104B maybe oriented as shown in series along a nerve N or oriented on oppositesides to the nerve tissue itself.

FIGS. 3C-D show an embodiment where dual EICCCs 230A, 230B interfacewith a nerve N but are driven with currents of opposite polarities suchthat when one is in a blocking phase, the other is in a non-blockingphase which resets the electrode for blocking once the current polarityis again reversed. With this configuration a constant block can bemaintained along the nerve N as illustrated in FIG. 3D. The electrodes230A, 230B interface with the nerve N via screens that sequesterdeleterious byproducts from dangerous electrochemical reactions toprotect the nerve N. The screens may include an ionically selectivemembrane such as an anion exchange membrane that only allows, forexample, anions to pass through it (but not cations).

FIG. 4A shows an embodiment of an EICCC electrode 240 in which anelectrode 104 is immersed in an electrolyte solution 102 which fluidlyin is contact with an ion-conductive material 106 such as a hydrogel,gel or other polymer that electrically contacts the nerve tissue N orarea proximal to the nerve tissue. The EICCC 240 electrode alsocomprises an electrically insulated enclosure 108 housing thetraditional electrode 104, electrolyte 102, ion conducting material 106with an aperture (near 110) to enable electrical contact with the nerveor area proximal to the nerve tissue. The electrolyte-hydrogel 107interface can alternatively be mediated by an ion selective screen or anion conductive polymer to sequester by products of any electrochemicalreactions to the aqueous region of the cell. The system furtheroptionally comprises a current delivery lead 112 between the currentsource 114 and the electrode 104. The current source 114 may be locatedexternal or internal to the body depending on the application need. Anexemplary embodiment of the EICCC 240 comprises a silver,silver-chloride (Ag/AgCl) electrode in a 0.9% saline solution in fluidcontact with an electrolyte saturated hydrogel (agar preparation with0.9% saline). In other examples, the electrode material may comprisemetal, carbon, conductive polymers materials and may be configured in ahigh surface area to volume configuration that may includeconfigurations such as open-celled foam configurations, sinteredparticle configurations, dendritic configurations or the like.

FIG. 4B shows a system 250 similar to that shown in FIG. 4A with theaddition of a reference electrode 111 in proximity to the electrode(working electrode) 104 to monitor voltage drop across the workingelectrode 104 for EICCC monitoring purposes. For example, to ensure thatthe electrode 104 is being driven under the desired conditions to ensurethat the proper electrochemical reactions are occurring.

FIG. 4C shows a system 260 similar to that shown in FIG. 4A with theaddition of a reference electrode 111 in proximity to the nerve tissueinterface to monitor voltage drop across the EICCC 260 to the nervetissue for EICCC monitoring purposes. For example, to ensure that theelectrode 104 is being driven under the desired conditions to ensurethat the proper electrochemical reactions are occurring.

FIGS. 4D-F show an embodiment of an electrode lead 212 configured toplug into and extend from a current source (not shown, near end 213)that might take the form of conventional IPGs (implantable pulsegenerators). FIG. 4F is a close-up view of 4E-4E of FIG. 4D. FIG. 4F isa close-up view of 4F-4F in FIG. 4D. This configuration could be similarto as that shown in FIG. 4A except that the nerve interface hydrogelshown in FIG. 4A is removed and the nerve tissue interface comprises ascreen or porous frit 404 which contains the electrolyte solution butallows ions to pass to the nerve tissue environment. A connector 213 tothe current source is shown with an electrically conductive portion ofthe electrode lead 213 that extends distal from the connector 213 to theEICCC 400 which couples the electron current to an ionic current viaelectrochemical reactions. The coiled electrode 402 converts electricalcurrent to ionic current in the EICCC 400 which is then transmittedtoward the distal portion of the lead which can be positioned inproximity to the target nerve tissue. Contact with the nerve tissueenvironment occurs via the ionic current which exits the screen/porousfrit 404 that can manipulate the nerve environment.

FIG. 4G shows a schematic embodiment of an EICCC integrated within ahermitically sealed enclosure 410 which contains the current source 412,battery 414 or power supply, and controller 416 to drive the EICCC 280.The EICCC 280 is directly connected to the current source 412 asillustrated and comprises a lead 418 from the current source 412 and anelectrode 420 immersed in an electrolyte solution 429 which fluidly isin contact with an ion conductive material 422 such as a hydrogel whichin turn contacts the nerve tissue N to be blocked. In this embodimentthe electrode element 420 of the EICCC 280 is located relativelyproximal to the current source 412 while the nerve contacting lead islocated relatively more distally from the current source 412 and extendsto the nerve location N. Also illustrated is the ion conductive conduit(e.g. hydrogel connector) 430, connector elementals 432, insulatedenclosure 420, and ion conducting electrode lead 428.

FIGS. 5A-B show an embodiment of an electrode configuration 500 in whichtwo electrode contacts are housed within the same electrically insulatedenclosure 504. The electrodes 502A, 502B are in ionic contact with ionconducting materials 510/pads 512 that interface with the nerve tissue Nand/or area proximal to the nerve. Each electrode 502A, 502B is inelectrical communication via its own conductive lead 506 that is drivenby the current source 508. The internal electrodes 502A, 502B can bedriven cyclically with opposite current polarities to provide a constantnerve block. The current source 508 may be configured to be implantablewithin the body such that any leads 506 and electrodes 502A, 502B arealso fully contained within the body. Alternatively, the current source508 may be configured to remain outside the body and can be connectedvia wired or wireless connections in this or other embodiments.

In some embodiments, a system is configured for nerve block at specificnerves. One such nerve is the dorsal root, and/or dorsal root ganglion(DRG) through which pain signals pass (FIG. 6A). The associated dorsalroot ganglia from each vertebral level correspond to specific dermatomesin the body (FIG. 7 ), and blocking pain signals at the DRG level canreduce pain sensation at the innervated dermatome for that specific DRG.Access to the DRG may be facilitated by initial introduction of a needletip to the DRG. A stylet or obturator in the needle may be used toprevent occlusion of the opening or inadvertent tissue damage due totissue entrapment by the needle opening. The needle tip may beradiopaque as to be visualized under fluoroscopy or other radiographicmeans. Removal of the stylet from the needle may also occur in orderinject contrast agent to enable visualization of the local structuresand to confirm location of the needle tip. A short acting nerve blockagent may also be applied to confirm that the targeted DRG body whenblocked will provide adequate pain relief. Upon confirmation that theneedle is positioned properly and the DRG body is the appropriate targetfor nerve block, the stylet can be removed if not already removed, and ablocking electrode terminating in an EICCC with a single or multipleelectrode-nerve interface contacts can be introduced through the needle.As shown in FIG. 6C the DRG can be accessed with a needle 600, and theneedle 600 can be used to penetrate the dura mater as shown.Alternatively, the needle 600 may be positioned just outside the duramater without puncturing the tissue. The introduced electrode may haveradiopaque markers to enable visualization under fluoroscopy. Theintroduced electrode may also be encased within a secondary sheath thatprevents deployment of anchoring elements until the distal end of thesheath is retracted from the distal end of the introduced electrode toexpose tissue-anchoring elements. The enclosed electrode may also havestress-relief features such as coils or slack in the electrode body toaccommodate bodily motion that might dislodge the electrode without suchfeatures. As shown in FIG. 6D and FIG. 6E, the electrode-nerve interfacecontacts 604 can then be positioned in contact or proximal to the DRGand the introducing needle 600 can be retracted to leave the electrodelead 602 and nerve tissue interface 604 in the desired position. Theproximal end of the electrode may be connected to a current source tobegin nerve block and ensure proper electrode positioning. Once theappropriate positioning and block have been achieved, the optionalelectrode sheath can be retracted to expose retention mechanisms such asbarbs or frictional elements that prevent dislodging of the electrodefrom its desired position. Optionally, a conductive gel may be appliedbetween the electrode contact or contacts and nerve interface to furthermitigate loss of conduction block if the electrode contacts moverelative to the DRG body. In some embodiments, if after deployment ofthe retention mechanisms, placement must be adjusted, the sheath can beadvanced to retract the retention mechanisms and the electroderepositioned before redeploying the retention mechanisms. Once theelectrode is properly positioned, the electrode can be disconnected fromthe current source and the insertion needle removed over the electrodetoward its proximal end. The sheath can then be removed in a similarfashion. The current source can then be reconnected to the leadconnector to confirm proper placement and that no dislodging hasoccurred with insertion needle and sheath removal. After an optionalevaluative period, the current source may be implanted into the patientbody and the electrodes and/or leads may be replaced with permanentelectrodes for long-term implantation. The current source may furthercontain a battery or energy storage unit and electronic circuitry whichenables the unit to be programmable from a programming unit that cancommunicate with the implanted current source when in proximity to thebody site close to the current source implantation site. The currentsource energy source may be optionally rechargeable by the externalcommunication unit such as by inductive charging. FIG. 6B shows anembodiment of a blocking electrode 100 positioned along a DRG tofacilitate nerve block along with lead 112 and current source 114. It isunderstood that nerve block may include hypersuppression of the DRG.

In an alternative embodiment, the current source may be located outsidethe body of the patient permanently or temporarily to enable nerveblock. The electrodes may also be removed once deemed unnecessary thusprovided a temporary nerve block as desired. The nerve block may also beturned on and off periodically by modulating the current source asrequired to enable sensation during procedures that require patientfeedback for example.

Block of DRG at specific dermatomes can be used to localize therapeuticpain reduction due to neuralgias, angina, ischemic pain, and complexregional pain syndrome (CRPS). In the case of angina, cervical spinallevel nerve roots C6 and C7 have been implicated as frequently involvedwith the associated pain, and localized DRG block at one or both ofthese levels (with or without block of additional DRG at other levels)could be used to help manage this pain. (Nakajima et al., Cervicalangina: a seemingly still neglected symptom of cervical spine disorder?,Spinal Cord, 2006 44:509-513.) For example, complex regional painsyndrome (CRPS) is often localized to a single limb and generating alocalized block can provide more specific pain block for the source ofpain. For example, the lumbar dorsal root ganglia at levels L2, L3, L4have been shown to be able to reduce knee pain on the ipsilateral sideof the spine using conventional DRG stimulation techniques. (Bussel etal., Successful Treatment of Intractable Complex Regional Pain SyndromeType I of the Knee With Dorsal Root Ganglion Stimulation: A Case Report,Neuromodulation, 2015 Jan. 18(1):58-61) Ischemic pain frequently islocalized particularly for patients with poor extremity circulation andmay be similarly mitigated by targeting the appropriate DRG levels forblock.

As described above and illustrated in FIGS. 6A-6D and FIG. 7 , an EICCCelectrode may be introduced in proximity to a DRG in order to blockand/or suppress the nerve tissue in the DRG to prevent distal painsignals from being registered by the individual. Furthermore, multipledorsal root ganglia may be targeted to generate unilateral and bilateralblocks or to adjust pain coverage based on pain presentation in thebody. EICCC electrodes may be placed at the target levels associatedwith the pain presentation and adjusted to tune the level of pain blockand coverage by adjusting the ionic current signal such as by tuning thecurrent amplitude at each DRG level targeted and in contact with anEICCC electrode. Localizing the pain block to specific regions of thebody can also help preserve normal sensory function in other regions ofthe body such that pain signals are not absent and can be used to signalan adverse situation and environmental conditions to the individual.

Compared to traditional SCS in which electrodes are placed along theposterior of the spinal cord in the epidural space, placement ofstimulating electrodes 800 in proximity to the lateral spinothalamictract (LT tract) (FIG. 8A) can leverage an EICCC to generate a nerveblock at the desired level (and/or spinal levels distal (away from thehead) to the EICCC since pain signals travel in the superior direction)and provide selective pain block depending on unilateral (left or right)or bilateral placement of electrodes 800. Electrode leads 802 may beplaced via a laminotomy (FIG. 8A middle, right) to enable access to theepidural space and then the electrodes leads 802 can be introduced andplaced into position along the lateral aspect or aspects of the spinalcolumn at the desired level or levels. Leads 802 may also be placedusing a percutaneous placement procedure with or without fluoroscopicguidance such as by using a Tuohy or similar needle 808 to introduce theelectrode lead 802 into the epidural space (FIG. 8B). The leads 802 canbe directed along the spinal column within the epidural space such thatthe lead 802 is between spinal nerve exit regions and the tissueinterface is in proximity to the lateral spinothalamic tract asillustrated in FIGS. 8C-8E. As seen in FIGS. 8C-8E, the electrode lead802 is positioned laterally to sit outside the lateral spinothalamictract such that the nerve tract can be blocked with the generated ioniccurrent from the electrode. Leads 802 may also be placed bilaterally tofacilitate bilateral block as each lateral spinothalamic tract carriespain information from the contralateral side of the body. The leads 802may then be connected to a current source to activate the nerve blockvia tissue interface 804 to ensure proper positioning and signal block.The lead 802 may then be disconnected from the current source and anoptional extension cable placed to connect the lead 802 to theimplantable current source. The current source may further contain abattery or energy storage unit and electronic circuitry which enablesthe unit to be programmable from a programming unit that can communicatewith the implanted current source when in proximity to the body siteclose to the current source implantation site. The current source energysource may be optionally wirelessly rechargeable by the externalcommunication unit such as by inductive charging.

In some embodiments multiple electrode leads such as illustrated in FIG.4D for example may be placed along the spinal cord, targeting thespinothalamic tract as shown in FIG. 8C. Furthermore, the electrodes maybe configured to have a multitude of tissue contacting regions whoseoutputs can be individually adjusted to optimize the nerve tissue block.An embodiment of an EICCC electrode is shown in FIGS. 10A-10C in whichmultiple tissue interfaces 404A, 404B are present on the electrode 402and are individually addressable. FIG. 10B is a close-up view of 10B-10Bof FIG. 10A. FIG. 10C is a close-up view of 10C-10C of FIG. 10A. In thisembodiment a dual system of EICCCs 400 are present and have parallellumens that are individually associated with each nerve tissue interfaceregion. In FIG. 10 the nerve tissue interface region and associatedEICCC are designated by matching letter labels, in this case A and B.Adjusting the current input and corresponding output at the distal endof the electrode can enable electric field shaping to facilitate desirednerve block while minimizing block of undesired structures. Analternative embodiment is captured in FIG. 5 in which individualelectrodes are also individually addressable and can be tuned to enabledesired block generation.

Using these methods of placement of blocking electrodes along the spinalcolumn to block the spinothalamic tract and the ability to tune theelectric field to generate nerve block and/or suppression, specifictargets for pain block can be facilitated. For example, trunk pain whichis moderated by the thoracic vertebral levels can be modulated byplacing leads along the thoracic spine while neck pain may be moderatedby providing block and/or suppression in the cervical spine. Upper limbpain may be moderated by providing a combination of cervical andthoracic level block and/or suppression while lower limb pain may bemoderated by a combination of lumbar and sacral level block and/orsuppression in the spine.

Generation of pain block can be used to facilitate peri-procedural painblock where motor control and non-pain sensations are desired. Forexample in labor and delivery of a child, one of the challenges withpain management particularly with epidural anesthesia is the reductionin ability to be sensate in the lower body. Due to the non-specificnature of the delivered anesthesia in the epidural space sensory, pain,and motor neurons are impacted. The epidural anesthesia can lead todifficulty with generating pushing force during the birthing process andcan lead to numbness a few hours after birth impairing motor abilitiessuch as the ability to walk. In some instances, epidurals are furtherimplicated in fetal and newborn health including breastfeedingdifficulty. Using the blocking electrodes described above to target thespinothalamic tract and/or dorsal root ganglia, the undesired pain canbe targeted without generating the side effects (or reducing sideeffects) associated with current epidural anesthesia techniques becauseonly the pain tracts are targeted and not any other motor or sensorytracts. Furthermore, in the case in which ionic current is delivered tothe nerve tissue in a reversible blocking fashion, the stopping of blockcan enable the patient to immediately be restored to normal painsensation if desired and any off-target block can be reversed enablingimmediate body function restoration.

Beyond central nervous system interventions, a safe direct current blockcan also be facilitated in the peripheral nervous system in which EICCCelectrodes are placed in contact or in proximity to peripheral nerves tofacilitate block. Specific pain targets include focal pain, phantom limbpain, neuroma pain, and neuralgias. Targeting the peripheral nervesproximally (i.e. closer to the spinal cord) from the site of pain forblock can suppress pain from the distal site. Specific to neuralgias,postherpetic neuralgia (after shingles) can be targeted based on thepresentation of the outbreak which will trace specific dermatomes. Fortrigeminal neuralgia, the trigeminal nerve (and/or trigeminal ganglionand/or trigeminal nucleus in the brainstem) can be targeted for block toreduce pain that commonly manifests as facial pain. Another target isthe glossopharyngeal nerve which produces pain in the neck and throat.Neuralgia in extremities such as the hands, arms, feet, and legs asfrequently caused due to diabetes-related neuropathies are alsopotential targets.

Outside of pain reduction, nerve block and activity suppression can beused to improve cardiovascular health in specific targeted ways.Hypertension which is implicated as a leading cause of cardiovasculardisease has been found to be able to be moderated by modulation of therenal nerves to reduce activation of the sympathetic nervous system.Current techniques exist to denervate or ablate these nerves using avariety of energy sources such as ultrasound and radiofrequency energy.(Krum et al., Catheter-based renal sympathetic denervation for resistanthypertension: a multicentre safety and proof-of-principle cohort study.The Lancet. 2009 373(9671):1275-1281. US Patent Application:2012/0016226) Using the tools described herein, selective nerve blockcan be used to facilitate activity reduction in the renal nerves andsympathetic nervous systems to facilitate reduction in hypertension. Asshown in FIG. 11 , the blocking electrode leads 1100A, 1100B contact therenal nerves to facilitate a block or suppression Also systematicallyillustrated is EICCC 1104 openly connected at 1106 to current source(not shown). The contact may also be configured in a cuff format tosurround the renal artery and provide a circumferential direct currentto the outer perimeter of the renal artery and block the nerve tissuesurrounding the artery. The delivered blocking current can also beadjusted to fit the individual physiological response to sympatheticnerve block which cannot be done currently with destructive methods suchas ablation.

Heart failure is another target disease state with known associationwith upregulation of the sympathetic nervous system. By using a blockingelectrode to moderate the sympathetic ganglia, particularly reducingactivity of the cervical sympathetic ganglia, excessive heart activitycan be reduced to mitigate overworking of the heart. Similar to dorsalroot ganglion access, the cervical ganglia may be accessed for block. Asshown in FIG. 12 , the relevant sympathetic ganglia including thecervical and stellate (cervicothoracic) ganglia are shown along withtheir innervation targets in the heart. Methods of access includeposterior access as well as through the pleural cavity.

Tachycardia or other tachyarrhythmias such as atrial fibrillation,atrial flutter, multifocal atrial tachycardia, paroxysmalsupraventricular tachycardia, ventricular tachycardia, and ventricularfibrillation for example may also be regulated by modulation of thesympathetic nervous system and can be influenced toward a more normalstate by targeting the cervical sympathetic ganglia (FIG. 13 ) toprovide a block of the sympathetic ganglia. Methods of access includeposterior access as well as through the pleural cavity.

Modulation of the parasympathetic innervation of the heart can be usedto regulate cardiac function. Stimulation of the vagus nerve is known tolead to bradycardia, or bradycardia, and suppression of heart rate.Conversely, by creating a vagal nerve block, the heart rate suppressingneural signaling can be reduced or shut down leading to increase inheart rate by reducing the vagal nerve signal. Particularly, the rightvagal nerve which innervates the sinoatrial node to help regulate heartrate can be blocked or suppressed to enable increase in heart rate. Asseen in FIG. 14 , an EICCC electrode 1400 can be placed around or inproximity to the right (and/or left) vagus nerve within the right sideof the neck and/or chest with an electrode lead 1402 running down towardan implantable current source 1404 shown in the right pectoral region.The electrode lead 1402 may be placed in the right subclavian region orother desired location and tunneled below the skin to the currentsource.

In addition to cardiovascular function, the nervous system plays asignificant role in regulating gastric processes including satiety (lackof hunger) and satiation (fullness). The vagus nerves innervate thestomach with the majority of signals to the brain reporting state ofsatiety and satiation. Using the EICCC electrode 1600, a block or nervesuppression of the vagus nerves can be generated to give the individuala heightened sense of satiety and satiation. Gastrointestinal nerves canalso be modulated to either increase or decrease GI transit time. Asseen in FIGS. 15-16 , an exemplary dual EICCC system is shown in whicheach vagus nerve is wrapped in a cuff-format tissue interface 1606 atwhich ionic current is deposited at the tissue site from the EICCCs 1600which are connected via electrode leads 1602 as well as to the currentsource 1604. The tissue interface may be moderated by a porous frit orother ionically conductive medium such as a conductive hydrogel aspreviously described herein. FIG. 16 is a close-up view of FIG. 15 nearthe gastro-esophageal junction region.

Sympathetic nerve suppression or block can also be used to regulatehepatic, gallbladder, and/or pancreatic function and influence glucoseand insulin production as shown in FIG. 17 . Suppressing or blocking thehepatic nerves can lead to increase insulin production and reduceresistance to insulin enabling management of adult onset or type 2diabetes in which insulin production is reduced or resistance to insulinfunction is increased. Using the EICCC electrode 1800, a block or nervesuppression of the hepatic nerves can be generated to increase insulinproduction and reduce insulin resistance. As seen in FIG. 18 , an EICCCsystem is shown in which the nerves around the hepatic artery and theartery are surrounded by a cuff-format tissue interface 1806 at whichionic current is deposited at the tissue site from the EICCC 1800connected via an electrode lead 1802 as well as to the current source1804. The tissue interface 1806 may be moderated by a porous frit orother ionically conductive medium such as a conductive hydrogel aspreviously described herein. In other embodiments, splenicneuromodulation could either improve depressed immune function, orreduce inflammation or hyperimmune function (e.g., in autoimmuneconditions such as SLE, rheumatoid arthritis, Crohn's, ulcerativecolitis), or other conditions.

Movement disorders including Tourette's syndrome, dystonia, Parkinson'sdisease (and associated rigidity), essential tremor, spasticity, andepilepsy can also be influenced by moderating neural tissue activity.These disorders and diseases are characterized by neural hyperactivityin specific parts of the brain, which can lead to the symptomaticpresentation. Targeting specific regions of the brain for blockincluding those captured in Table 1 below can be used to help manage apatient's symptoms. It is recognized that blocking of these targetscould be either unilateral or bilateral.

TABLE 1 Movement disorders and brain region targets for nerve tissueblock for symptom reduction. Disease, Disorder Region of the BrainTourette's 1. anteromedial globus pallidus syndrome 2. Ventral anteriorthalamus 3. Ventrolateral motor part of thalamus Dystonia 1. Internalsegment of the globus pallidus (GPi) Parkinson's 1. Internal segment ofthe globus pallidus (GPi) disease 2. Subthalamic nucleus (STN), 3.Pedunculopontine nucleus (PPN), 4. Vim (ventro-intermediate nucleus) (asubdivision of the thalamus) Essential Tremor 1. Thalamus (Vim:ventro-intermediate nucleaus) 2. posterior subthalamic area (PSA)Epilepsy 1. Anterior nucleus of the thalamus 2. Other identifiedepileptogenic foci

Similarly, psychiatric disorders including treatment resistantdepression (TRD), anxiety, obsessive compulsive disorder (OCD), andpost-traumatic stress disorder (PTSD) have are targets for neural blockto reduce symptoms from these conditions. Targeting specific regions ofthe brain for block including those captured in the Table 2 below can beused to help manage a patient's symptoms. It is recognized that blockingof these targets could be either unilateral or bilateral. Otherdisorders that can be treated can include, for example, schizophrenia,schizoaffective disorder, bipolar disorder, mania, alcoholism, substanceabuse, and others.

TABLE 2 Psychiatric disorders and brain region targets for nerve blockfor symptom reduction. Disease, Disorder Region of the BrainTreatment 1. Subgenual cingulate cortex, Resistant 2. Inferior thalamicpeduncle, and Depression 3. Nucleus accumbens Anxiety 1. Nucleusaccumbens OCD 1. Ventral internal capsule 2. Ventral striatum PTSD 1.Basolateral amygdala

Chronic pain is another target in which specific regions in the brainhave been implicated in affecting chronic pain. One such region is thethalamus which is the entry point for pain signaling to the brain.Specific regions in the thalamus have been identified as targets forneural activity reduction to reduce chronic pain as shown in Table 3below. It is recognized that blocking of these targets could be eitherunilateral or bilateral

TABLE 3 Brain region targets for nerve block for pain reduction.Disease, Disorder Region of the Brain Chronic pain 1. Ventromedialthalamic nuclei 2. Intralaminar thalamic nuclei

In some embodiments a system is configured for generation of nerve blockfor disorders and diseases that can be addressed by reducing neuralactivity in specific regions of the brain responsible for the specificdisorder. Neural activity reduction can be facilitated by directlyblocking and reducing activity of specific neurons as well as byblocking pathways along which excessive neural signaling is occurring.In some embodiments, this system for deep brain block (DBB) comprisesall or some of the steps of identification of the anatomic target sitefor block, creating an access site to the exterior of the brain tissue,creating a path through the brain tissue to the target site, evaluatingthe suitability of the target site for block, adjusting or refining thelocation of the target site, providing nerve block at the target site,and adjusting the nerve tissue block strength or location. Practically,this process may be implemented using techniques known in the field ofdeep brain stimulation (DBS) in which a target anatomic site isidentified using a combination of imaging techniques such as but notlimited to magnetic resonance imaging (MRI) including functional MRI(fMRI), computed tomography (CT), PET scanning, and/or x-rays. This sitecan then be accessed using stereotactic techniques to register anidentified region from imaging to the physical anatomy on the patient. Aframe may be fixed to the patient's head and skull to allow for spatialregistration during the procedure. An access site to the brain tissue inthe form of a burr hole or craniotomy can be formed with or withoutadditional access tools fixed to the skull such as insertion cannula andadvancement/retraction equipment to access the target site. Advancementof a nerve tissue activity measurement probe through the brain tissue tothe target site may be used to enable evaluation of the suitability ofthe brain region. This probe may record neural activity to determinethat the measured signals are consistent with that of tissue requiringblock. If the signal characteristics indicate that the location is notoptimal or appropriate for block, the probe may be adjusted until thecorrect location is identified. The measurement probe may be exchangedwith the blocking electrode which can then be inserted with the activeportion of the electrode positioned within the target site. Activationof the blocking signal can then be used to assess efficacy of the blockas well as to tune the strength of the signal. The blocking electrodecan then be fixed to the skull to maintain the active portion's (e.g.,region delivering ionic current) position at the target site. Anextension lead can be connected to the affixed blocking electrode andconnected to an implantable current source, similar to an implantablepulse generator (IPG), whose output signal can be adjusted to facilitateoptimal symptom reduction. Blocking electrodes may be implantedunilaterally or bilaterally as the contralateral side of the body isaffected by specific anatomic target sites.

FIG. 9A shows an electron-ion current conversion cell (EICCC) electrode900 configured to interface with a deep brain block (DBB) target in thethalamus. The nerve tissue interface 904 contacts and provides block tothe target site in the thalamus while an electrode lead 902 provides aconduit between the thalamus and the exterior of the skull. An extensionport in the skull anchor 910 allows for communication between thecurrent source 908 and the electrode lead 902 via an electrode extension906 which can connect electrically with the port and current source 908.Within the lead 902 itself the EICCC blocking electrode comprises aninternal electrode 916 such as an Ag/AgCl wire which converts electroncurrent to ionic current in an ion conductive medium 918 such as salineand generates ionic current at the nerve tissue interface 904 via anionically conductive material such as a porous frit 920 designed toallow ions to flow through it to generate a block at the nerve tissuesite. The ionically conductive medium 918 and/or tissue interfacematerial may also comprise a hydrogel or other ionically conductivematerial as described elsewhere herein.

Specific to epilepsy, electrocorticography (ECoG) may be performed toidentify the epileptic focus or foci for targeting of electrodeplacement and nerve block in that location. The implanted blockingelectrode may be used to block or suppress nerve tissue activity ondemand by the user during an epileptic fit or when sensing the onset ofan epileptic fit. Moreover, the system including the blocking electrodemay be configured to alternatively lower the field potential of acluster of neurons prone to causing epileptic fits such that epilepticfits may be prevented instead of being reacted to when they are about tooccur or when they are occurring. In another embodiment, the blockingelectrode is combined with a measurement or sensing electrode such thatthe activity of the neuron cluster or clusters comprising the epilepticfocus or foci are monitoring and when activity indicative of onset of anepileptic episode is measured, the system can automatically generates ablock to reduce activity of the target cells in a closed-loop fashion.In FIG. 9B an embodiment of a blocking/suppressing electrode 950 with anintegrated sensing electrode 922 is shown in which a sensing electrode922 is in proximity to the nerve tissue interface 904 such that sensingof the target neuron activity can occur and the signal from the sensingelectrode 922 feeds back to the current source 908 which can beactivated based on the sensing electrode signal to generate an ioniccurrent at the nerve tissue 904 interface to disrupt or prevent onset ofan epileptic fit. The sensing electrode 922 can include an insulatedconductive path to electrode extension 924. In other embodiments, theblocking electrode may also serve as the sensing electrode 922 (e.g.when blocking current is not being applied). An electrode for blockingtissue to treat epilepsy may be configured as straight probe which isimplanted deeper than the cortical surface, or may be configured as aepi-cortical electrode (e.g., by having a planar or conformal element).

Disclosed herein in some embodiments are systems and methods to maintaindesired electrochemical reactions by monitoring signals indicative ofthe reactions occurring to modify the reaction generation conditions.Not to be limited by theory, traditional alternating current stimulationof neural tissue typically delivers a relatively low amount of chargethrough conventional electrodes (e.g., platinum electrodes). However, insome embodiments, high charge density electrodes including thosedescribed elsewhere herein deliver relatively greater amounts of chargecloser to and beyond, and in some cases far beyond, the Shannon limit.Control systems and methods such as those disclosed herein cansurprisingly and advantageously allow for the safe delivery of suchcurrent to tissue.

In some embodiments, a system which delivers ionic current driven by anelectrochemical reaction can include a monitoring system, e.g.,including a hardware and/or software controller configured to measurethe voltage required to generate the electric current to drive theelectrochemical reaction. If the voltage crosses a threshold, e.g., apredetermined threshold, the controller can adjust (e.g., increase ordecrease) the current output to bring the voltage level into anacceptable range relative to the threshold voltage level. For example,if the voltage required to maintain a specific current level becomes toohigh, the current level may be reduced to the point that the voltagefalls below the defined threshold. In some embodiments, if the voltagerequired to maintain a specific current level becomes too high, thecurrent level may be set to zero. In yet another alternative system, ifthe voltage required to maintain a specific current level becomes toohigh the current level may be reversed.

In some embodiments, the current may take the form of a waveform suchas, for example, a square wave or similar waveform between a firstelectrode (e.g., a working electrode) and a second electrode (e.g., acounter electrode) in which current is passed between the two electrodeswith opposite polarity relative to a single electrode depending on theposition within the waveform cycle. The voltage waveform required todrive the current between the electrodes may fall within an upper andlower voltage threshold limit. Over time, if the underlyingelectrochemical reaction is found to drift because of variousconditions, the driving voltage waveform required to maintain the targetcurrent waveform may also drift. If the excursions/deviations from thetarget thresholds are significant enough, this may be indicative ofundesired electrochemical reactions occurring. The voltage thresholdlimits and associated voltages may alternatively or additionally bemeasured between the working electrode and reference electrode todirectly assess the voltage drop across the workingelectrode—electrolyte interface to assess the electrochemical reactionsand potentials across that interface. To prevent these excursions intoundesirable zones, the current delivered may be adjusted to reduce thedriving voltages as described above. Alternatively, the voltageexcursions may be due to changes in electrochemistry. For example in asystem in which a reaction occurs where the same target amount of chargeis transferred from one electrode to a second electrode and back to thefirst electrode, the net charge over time may drift from zero (e.g.,become unbalanced) due to imperfect charge accounting. This in turn maylead to changes in voltage required to generate the desired current andbe indicative of undesired electrochemical reactions occurring. Thedrift in net charge transfer from a target level may be countered insome embodiments by monitoring the driving voltage, and generating acontrol loop that generates additional charge on an electrode which hasbeen detected via its driving voltage characteristics to be deficient inreactants. For example for a Ag—AgCl system, depletion of available AgClon the working electrode can present as a negative dip in voltage whendriving it cathodically as the lower reaction potentialAgCl(s)+e−↔Ag(s)+Cl— reaction is no longer available and other higherreaction potential reactions take place requiring higher drivingvoltages. In this case, if a higher voltage is detected during thecathodic phase of the waveform, additional charge may be imparted to theworking electrode during a subsequent anodic phase by increasing theduration, amplitude, or both, of the current delivered to the workingelectrode.

FIG. 19 illustrates a driving voltage waveform and positive and negativethresholds over a period of time. As shown, the negative threshold iscrossed/breached due to negative voltage dips before time point 2600.After 2600, the negative dips are no longer present and can be addressedby adjusting the target current level, and/or by adjusting distributionof charge transfer between the working and counter electrodes. Forexample, additional charge to generate more reactant material can betransferred during the anodic phase of the cycle for the workingelectrode.

FIG. 20 illustrates a driving voltage waveform, and positive andnegative thresholds over a period of time. As shown, the negativethreshold is crossed/breached due to negative voltage dips which maypresent characteristically as dips or spikes on top of a moremonotonically increasing or generally flat voltage waveform, and may beindicative of undesired reactions taking place.

FIG. 21 illustrates schematically a voltage and current versus timegraph illustrating an electrode annealing process in which the currentamplitude is being ramped to a set target while the driving voltage isheld below a set threshold. If the driving voltage is not exceeded for agiven current amplitude, the current can be incrementally increasedupward to the target current. If the driving voltage is exceeded for agiven current amplitude, the current can similarly be incrementallydecreased until the voltage threshold is no longer exceeded. Multiplecycles at a given current amplitude can be used to determine whether ornot the system is stable at that current level and duration as assessedby staying within the voltage thresholds before incrementing the currentup toward the target current. In some embodiments, at least about,about, or no more than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30,35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 500, 1,000, or moreor less cycles can be utilized, or ranges incorporating any two of theforegoing values. The voltage threshold for a series of cycles at atarget current may also be set to fall within a driving voltagetolerance to be deemed stable to determine whether or not the annealingprocess has been successful.

Also disclosed here are systems and methods for blocking neural tissuewith direct current. The systems can allow for indefinite direct currentdelivery (e.g., without requiring recharge reversal of current). Wateror other suitable media such as normal saline can be used as the primaryredox reactant in some cases; the reservoir can be refilled with wateror other media as needed. In some embodiments, one, two, or more ventscan be present to allow the venting of gas generated by the redoxreaction. In some embodiments the vent may comprise a gas permeable byliquid impermeable membrane to enable venting of gas but retention ofliquid within the container. The DC generator may have voltagesufficient to drive potentially large lead/catheter impedance. Thesystem can also include one, two, or more pumps to cycle media, such aswater, through a pH neutralizer to maintain a desired, e.g., neutral pHof the bath. The system can also include pH sensors to detect the pH ofthe bath, and allow for modifications, e.g., buffering if needed. Thebath may further comprise a pH-buffered solution to maintain a nominallyconstant bath pH. FIG. 22 illustrates a system that can include anerve-tissue interface operably connected to a catheter configured tohold a liquid. Also shown is a reaction chamber including a reactionelectrode that can have a high surface area, which can be partially orentirely surrounded by a redox reactant (e.g., water) as previouslynoted. The chamber can also include a pH sensor. The chamber can beoperably connected to a pump and reservoir of pH neutralizer that can besealed from the chamber normally, and a valve or other reversiblepassageway opened when the pH falls outside of a pre-determinedthreshold value. The chamber can also include an agitator (e.g., anultrasonic probe) to promote release of bubbles from the electrode. Thebath may also include a surfactant to reduce the adhesion of bubbles tothe electrode when formed. The reaction electrode can be operablyconnected to a DC generator. The DC generator can also be connected to apotential second unit to facilitate return current.

In some embodiments, a DC blocking electrode tissue system can includereplaceable electrode material. Spent reacting metal (or other material)can be optionally removed over time, and fresh reactant materialsupplied to the reaction chamber. This can advantageously allow forone-way delivery of DC current without requiring a reversal/rechargephase. FIG. 23A illustrates a system including a reaction chamberincluding a reaction material. A rotatable member such as a spool with atether (including or operably attached to reaction material), conveyorbelt, or other mechanism can move fresh reactant material into (andspent reactant material out of) the reaction chamber as shown. Alsoillustrated is a catheter configured to convey the DC current to atissue interface. Also illustrated is DC generator operably connected tothe reaction chamber and/or the spool.

In some embodiments, disclosed herein is a separated interface nerveelectrode that can include an integrated sensor for detecting theelectrochemical status of a reaction/working electrode as shownschematically in FIG. 23B. A sensor can measure one, two, or morevariables indicative of the working electrode state such as, forexample, pH, mass, or voltage. In some embodiments the sensor may be areference electrode such as an Ag—AgCl reference electrode or platinumreference electrode to enable measurement of the potential between theworking electrode and the reference electrode to probe theelectrochemical reactions occurring at the working electrode—electrolyteinterface. Such leads/electrodes can have a relatively short length toreduce impedance. The lead lengths may range in length from 0 to 2 cm, 2to 4 cm, 4 to 8 cm, or 8 to 12 cm in length, or ranges incorporating anytwo of the aforementioned values. Furthermore the combination of thelead geometry and ionically conductive media within the lead may beconfigured to have an impedance value less than 1 kOhm/cm length orbetween 1-3 kOhm/cm or above 3 kOhm/cm.

FIG. 24 illustrates that systems and methods can utilize battery-typechemistries to deliver DC current to tissue, such as lead-acid battery,nickel-cadmium, nickel metal hydride, lithium ion, lithium polymer,zinc-carbon, biobatteries, or other types of battery chemistries.Systems can include a DC generator operably connected to one, two, ormore reaction chambers that can include battery chemistry-typereactants. For example, the reactant could be lead/lead oxide and theredox reactant could be sulfuric acid and/or water as illustrated. Amembrane or other unit denoted at A can prevent passage of deleteriouscomponents into the catheter/lead connected to tissue (e.g., a cation oranion-selective membrane).

FIG. 25 illustrates schematically a SINE-type electrode modified toallow for attachment at the site of the patient to reduce the length andthe impedance of the catheter. For example, a DC generator is operablyconnected to a wire connected to a reaction chamber (e.g., electrodesystem/charge generator including an electrode and electrode bath), inturn connected to a liquid catheter/tube configured to deliver DCcurrent to a target tissue location. While one or more of theaforementioned components could be external or internal to the patient,in some embodiments as shown only a small length of liquid catheter/tubesits between the electrode system and target tissue location in thepatient to reduce length and impedance. In some embodiments themajority, or at least about 50%, 60%, 70%, 80%, 90%, or more of thelength of the liquid catheter/tube may sit internal to the patient'sbody. In some embodiments, less than about 5 cm, 4 cm, 3 cm, 2 cm, 1 cm,or less of the length of the liquid catheter/tube are internal to thepatient.

In some embodiments, the system could be completely wearable to promotemobility of the patient. The system could include a strap, adhesive,band, or other element for attachment to the desired body surface, suchas the scalp, neck, upper or lower extremities, torso, or abdomen forexample. The lead/catheter could interface percutaneously as shown atthe desired anatomical site, or transcutaneously in other embodiments.FIG. 26A illustrates a wearable system including a DC generator, wire,and reaction chamber, with a portion of the lead/catheter implanted atthe desired anatomical site. FIG. 26B illustrates a bandage-style systemthat is local to the site of treatment (e.g., nerve block). FIG. 26Cshows a schematic embodiment of such a wearable device with twodifferent lead exit configurations where the lead exits the narrowaspect of the system and where the lead exits the wider aspect of thesystem and can be directly inserted into the patient body. The lead maybe configured to be detachable from the rest of the system to enableease of insertion into the patient body prior to connecting to the restof the wearable system.

In some embodiments, disclosed herein are methods of treating pain orother conditions by cycling DC block at a plurality of locations spacedapart from each other. For example, electrodes could be present at sitesA and B shown schematically in FIG. 27A, supplied by a DC generator.Variables v(t) (voltage over time) or i(t) (current over time) as shownin FIG. 27B could have very long biphasic cycles. As illustrated in FIG.27C the time of each phase of the biphasic wave t_(1/2) could be, forexample, at least about 0.1 sec, 1 sec, 5 sec, 10 sec, 20 sec, 50 sec,100 sec, 500 sec, 1000 sec, 5000 sec, or longer, or ranges incorporatingany two of the foregoing values. Blocking tissue part of the time caninvolve an electrode directly beneath or proximate target tissue to betherapeutically beneficial in a person in need thereof. The DC currentblock can in some embodiments, be in the vicinity of electrodes A or B,thus providing continuous or near-continuous block in the tissue. Insome embodiments, 3, 4, 5, or more spaced apart electrodes withoverlapping charge waveforms can be utilized to advantageously promotecontinuous nerve blockade as shown in FIG. 27D.

Also disclosed herein are systems and methods of controlling DC outputcurrent amplitude based on measuring a variable indicative ofelectrochemical state for a DC blocking electrode system. This canadvantageously promote safe use of DC current to ensure operation onlyin the electrochemical range (e.g., reaction types) that are safe forthe health of the tissue as well as the electrode. The variable couldbe, for example, one, two, or more of: voltage, pH, temperature, orothers. FIG. 28A schematically illustrates a DC current system includingan optional reference electrode for voltage monitoring. In the simpleexample shown in FIG. 28B, electrode voltage increases with continued DCcurrent delivery. Current can be halted once the voltage reaches athreshold maximal value indicating that a different chemistry (e.g.,electrolysis of water) may be possibly occurring. In some embodiments,the system can be more complex to allow less interrupted delivery bydecreasing or otherwise modulating output current to keep the voltagewithin a desired operating window. Output can be controlled, forexample, with a Proportional-Integral-Derivative (PID) controller.Net-imbalanced charge delivery can be desirable in some cases to keepoperating voltage within the desired window.

Some embodiments can also include an annealing process for an electrode,e.g., a silver-silver chloride electrode without or without a coating,operably connected to a DC generator. The output current can begradually increased in a cyclical fashion, while monitoring the voltage.The voltage can be kept within a desired range with upper and lowerthreshold bands as shown in FIG. 29 which limits the electrochemistryoccurring at the electrode site (e.g., to a silver-silver chloridereaction as opposed to water electrolysis).

Also disclosed herein in some embodiments are single-fault safe DCsystems and methods. The systems can methods can involve very largeseries capacitors, such as about or at least about 5,000, 7,500, 10,000,or more microfarads (mfd), as shown schematically in FIG. 30A. Chargeaccounting can be performed so a known value is delivered in eachdirection, such as utilizing any number of the following: programmedamplitude and duration of delivery; measured delivery using voltageacross a sense resistor; monitoring voltage out (with or withoutadditional (e.g., third or fourth) reference electrodes as shownschematically in FIG. 30B; monitoring circuits to have control ofswitches to halt or slow current delivery as shown schematically in FIG.30C; and/or performing monitoring by an independent microcontroller orlogic device to promote tolerance to single (or multiple) faultconditions.

Additionally disclosed are electrode systems and methods for makingthese systems which can deliver direct current safely to tissue.Specifically, a silver-silver chloride electrode configuration isdisclosed comprising a silver (Ag) substrate with an attachedsilver-chloride (AgCl) layer (FIG. 31 ). The AgCl layer may be depositedon the surface through a chemical deposition process. Alternatively orin addition, the AgCl layer may also be grown on the silver substratethrough an electrochemical process of immersing the silver substrate inan electrolyte solution containing chloride ions (Cl—) and drivingcurrent through the substrate to facilitate a chemical reactionoxidizing the silver atoms in the substrate allowing them to bind to thechloride ions to generate silver chloride as previously described:Ag(s)+Cl⁻⇔AgCl(s)+e ⁻

In some embodiments, the electrodes may be in any desired shape,including but not limited to generally flat, or rounded, such as in acylindrical shape. In one non-limiting embodiment, the electrode caninclude dimensions of about 1.4 mm in outer diameter with a length ofabout 3.5 mm. In another embodiment, the electrode may comprise a flatdisk, with a diameter of about 3.6 mm. The electrode may also have anoblong or pill shape. The electrode surface area may be, for example, inthe range of less than about 5 mm², about 5 to 10 mm², about 10-15 mm²,about 15-20 mm², greater than 20 mm², or ranges including any two of theaforementioned values (e.g., between about 5 mm² and about 20 mm²). Alayer of silver chloride on the silver substrate may be generated with,for example, a thickness of less than about 1 micron, about 1 to 3microns, about 3 to 5 microns, about 5-10 microns, or about 10 micronsand greater, or ranges including any two of the aforementioned values(such as between about 1 micron and 10 microns), to enable sufficientdirect current and charge delivery as therapeutically necessary. In oneconfiguration, a cylindrical electrode of diameter about 1.4 mm andlength about 3.5 mm is prepared with an about 10 micron thick layer ofsilver-chloride to enable delivery of up to about 5000 mA-seconds ofcharge such as a specific setting of about 5 mA of current for about 10seconds. When the reaction is run in reverse with an appropriatecounter-electrode, the electrode may be regenerated to enable prolongedcycling and use of the direct current in the body.

Silver chloride can be created on pure Ag by the application of directcurrent through an electrolyte bath (FIG. 32 ). As seen in FIG. 32 acounterelectrode and working electrode are shown immersed in anelectrolyte bath and connected to a power supply which drives apotential across the two electrodes. In one configuration, theelectrolyte bath includes chloride ions such as a saline solution, forexample 0.9 wt % saline. The counterelectrode and working electrode mayboth be silver, or just the working electrode may be silver. Withapplication of a driving voltage, a current is generated and silver onthe working electrode can be converted to silver chloride creating alayer of silver chloride on the silver substrate.

A simplistic approach could apply direct current and calculate, by meansof coulometric measurement, the total charge needed to produce enoughAgCl on the electrode such that the longest cathodic pulse attherapeutic current levels would not deplete the electrode. However, thesimplistic approach fails to address the properties of AgCl which affectboth its ability to easily participate in the symmetric electrochemicalreaction while remaining with a safe driving voltage range below theelectrolysis potential threshold. It can be important in someembodiments that the electrode system keeps the ionic current flowisolated to the Ag to AgCl electrochemical reaction to substantiallyprevent the production of potential harmful byproducts. Controlling thevoltage potential applied to the electrodes can be the primary means ofselecting the electrochemical reaction as different reactions take placeat different potentials. An AgCl electrode which does not have thecorrect properties can require voltage potentials higher than anallowable threshold value to maintain the prescribed current flow andduration. As a result, the electrochemical reaction can becomeuncontrolled, leading to the generation of potentially harmfulbyproducts.

One initial step can be to generate a layer of silver chloride on thesilver substrate. To do this in a controlled fashion that does not causeelectrolysis of the aqueous solution, a maximum current may be specifiedwhich may be the target current for therapeutic operation of theelectrode or the maximum therapeutic current for the electrode. Themaximum current may be in the range of, for example, about 0 to 3 mA,about 3 to 5 mA, about 5 to 7.5 mA, about 7.5 to 10 mA, or about 10 mAand higher, or ranges including any two of the aforementioned values. Adriving voltage can then be applied between the counterelectrode andworking electrode to generate a silver chloride layer on the workingelectrode. A target total charge can be specified to generate the targetamount of silver chloride on the electrode surface. The build period ofthe electrode can be specified as well as an etch back period whereinthe current is driven in reverse to remove some of the formed silverchloride to generate a more robust formation of silver chloride on theelectrode surface. One configuration could include a 60 second buildperiod with a 10% etch back period, for example, wherein 10% of thebuilt AgCl layer is then removed prior to the next build period. Othercombinations of build and etch back or removal periods can be used togenerate the AgCl on the silver substrate.

As shown in FIG. 33 for trace A (solid line), the driving voltageapplied can be positive corresponding to building of AgCl on the workingelectrode. After the prescribed build period a removal or etch backperiod occurs, then the next build cycle occurs until the total chargeand target AgCl layer has been deposited at which the build processterminates as denoted by the ‘X’. Because the absolute values of drivingvoltage thresholds were not reached in trace A, the driving voltage didnot need to be adjusted during the AgCl generation process. However, inFIG. 33 for trace B (dotted line), the driving voltage upper thresholdwas reached and an algorithm stored in the controller can cap thedriving voltage at an upped threshold level by reducing the current usedto build the AgCl. The build period can be followed by a removal or etchback period as described and this process continues until the targetcharge is deposited in the form of AgCl on the working electrode.

Once the silver chloride has been generated on the electrode, thedriving voltages to convert the AgCl to silver and vice versa may stillexceed the electrolysis potential leading to potentially dangerousconditions if used in proximity to tissue. To condition the electrodesuch that it can operate in a safe range with driving voltagesmaintained below the electrolysis potential, the electrode can be cycledin a specific manner.

Cycling of the silver/silver-chloride reaction at fixed currentamplitude and fixed durations has been demonstrated to lead to decreasesin peak driving voltages with increasing number of cycles as shown inFIG. 34 and can result in driving voltages below the electrolysisthreshold. However, the approach of fixing the current amplitude andduration can in some cases lead to generation of undesired and unsafebyproducts if the driving voltages exceed the electrolysis threshold asseen by the peak voltages which exceed or cross the driving voltagethreshold upper and lower limits, potentially leading to generation ofundesirable reaction by products. In some embodiments, the electrode canbe prepared in a manufacturing bath and then the electrode is removedfrom that bath prior to use in the target device bath or in the bodydirectly at which time the driving voltages can be reduced and withinthe desired range.

To mitigate generation of undesirable byproducts, cycling algorithmshave been developed that can be executed by a hardware or softwareprocessor, which cycles the electrode in a build and removal cycle toobtain the desired current amplitude and duration that can be repeatedlycycled without exceeding set driving voltage thresholds which may be theelectrolysis potential or otherwise. The process occurs through, forexample, two steps, a formation step and a stabilization step.

The formation step involves the repeated cycling of current which buildsa layer of AgCl for a specific period then removes the added AgCl. Theamount of AgCl deposited is limited by the current level which is inturn limited by the maximum voltage limit or driving voltage upperthreshold. There may also be a minimum voltage limit or driving voltagelower threshold. As the AgCl is repeatedly added and removed theunderlying structure of the AgCl is transformed allowing it to sustainmore current at the fixed driving voltage level. Under certainprocesses, these changes can be observed as microstructural changesvisible on the surface of the electrode. The formation phase continuesuntil the current level that can be sustained meets the prescribedvalue.

One embodiment of an algorithm is as follows:

-   -   a. Apply anodic current to the electrode for the prescribed        period. During this time, measure the peak positive voltage over        the duration.    -   b. Apply cathodic current to the electrode until the total        charge applied during the anodic phase has been removed. During        this time, measure the peak negative voltage over the duration.    -   c. Analyze the peak voltages and adjust the current to be        applied on both the anodic and cathodic phases. If the magnitude        of the peak voltage is below the voltage limit, then the current        magnitude is increased by a fixed proportion up to the        prescribed current limit. If the peak voltage magnitude exceeds        the voltage limit then the current magnitude is decreased by a        proportional amount.    -   d. If the anodic current has reached the prescribed current        value then move to the stabilization phase. Otherwise continue        to repeat the cycling process.

In FIG. 35 a working electrode and counterelectrode formation areprocessed in the formation step where the current level starts at arelatively low value and rises with each cycle when the driving voltageupper threshold is not exceeded. As seen by the solid arrows, when thedriving voltage upper threshold is exceeded for a given current level,the applied current level for the next cycle is reduced as shown withthe open arrow. The duration of the positive current for the workingelectrode is set to the target duration and the final amplitude is thetarget amplitude. Both may be configured to vary in other embodiments ofthe algorithm.

The stabilization step can also involve the repeated cycling of currentwhich builds a layer of AgCl for a specific period, then removes theadded AgCl. The amount of AgCl deposited is fixed and determined by thecurrent and duration. As the AgCl is repeatedly added and removed, theunderlying structure of the AgCl is transformed, reducing the voltagepotential required to pass the prescribed current for the duration. Thestabilization phase continues until the cycle-to-cycle voltage variationfalls below a preconfigured value. As seen in FIG. 35 the stabilizationphase may include a substantially consistent current amplitude with eachcycle and driving voltages whose peak levels are consistent within apre-defined variation value.

One embodiment of an algorithm is as follows:

-   -   e. Apply anodic current to the electrode for the prescribed        period. During this time measure the peak positive voltage over        the duration.    -   f. Apply cathodic current to the electrode until the total        charge applied during the anodic phase has been removed. During        this time measure the peak negative voltage over the duration.    -   g. Maintain (e.g., in a memory) a list of the previous N peak        voltages. The number of samples, N, is the configured stability        period.    -   h. If the variation in peak anodic voltages is below a        configured value the electrode formation process is complete.        Otherwise, continue to cycle current. Alternatively, the        magnitude of the peak anodic voltages are below a configured        value until or when the electrode formation process is complete.

In some embodiments, the electrode could have a working surface area of,for example, about, less than about, or no more than about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100 mm², or moreor less, or ranges including any two of the foregoing values.

In some embodiments, the maximum current limit could be, for example,about, less than about, or no more than about 0.1, 0.2, 0.3, 0.4, 0.5,1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mA, or more or less, or ranges includingany two of the foregoing values.

In some embodiments, the voltage limit could be, for example, about,less than about, or no more than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8. 1.9, 2, 2.5,3, 3.5, 4, 4.5, 5V, or more or less, or ranges including any two of theforegoing values.

In some embodiments, the voltage variation limit could be, for example,about, less than about, or no more than about 0.1, 0.5, 1, 5, 10, 15,20, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250 mV, or more or less,or ranges including any two of the foregoing values.

In some embodiments, the time period limit could be, for example, about,less than about, or no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40,45, 50, 55, 60 seconds or more or less, or ranges including any two ofthe foregoing values.

In some embodiments, the stability period could be, for example, atleast about, about, or no more than about 2, 3, 4, 5, 6, 7, 8, 9, 10,15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 500,1,000 cycles, or more or less, or ranges incorporating any two of theforegoing values.

In some embodiments, the build period could be, for example, at leastabout, about, or no more than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 500, 1,000seconds, or more or less, or ranges incorporating any two of theforegoing values.

In some embodiments, the build etch-back period could be, for example,at least about, about, or no more than about 1%, 2%, 3%, 4%, 5%, 6%, 7%,8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%,23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more orless, or ranges incorporating any two of the foregoing values.

In alternative embodiments, the build charge might be up to about 2500,3000, 3500, 4000, 4500, or 5000 mA-seconds or higher than 5000mA-seconds, such as 5500, 6000, 7000, 8000, 9000, 10000 mA-seconds, ormore, or ranges including any two of the aforementioned values.

In some embodiments, such as in the algorithms disclosed, for example,the electrode can be conditioned in a manner that allows for delivery ofthe target current amplitude for the desired duration with a drivingvoltage below a set threshold such as the electrolysis potential, forexample. The algorithm also limits the amount of time the electrode isexposed to voltages above the driving voltage upper threshold which canlead to generation of deleterious by products that can damage tissue.

FIG. 36 shows the change in microstructure that can occur after buildingan AgCl layer on a bare silver electrode and after performing theformation and stabilization steps to condition the AgCl-coatedelectrode. These microstructural changes can include formation ofAg—AgCl “islands” that readily transition between the Ag and AgCl formsand increase surface area for electrochemical reaction.

While embodiments have been described for building and conditioning anelectrode so that the driving voltage remains below a set thresholdwhich can be a safety threshold such as the electrolysis potential oranother threshold set as desired such as by incorporating safetyfactors, the system may still encounter scenarios that tend to push thedriving voltage out of the desired target range. For example, the chargeexchanged between the working and counter electrodes may be slightlybiased such that more charge is being deposited on the counter electrodethan on the working electrode with each cycle. Over many cycles this maystrip the working electrode of active, conditioned AgCl or anothersubstrate causing the magnitude of the driving voltage to rise. FIG. 37shows a driving voltage which started to exceed the driving voltagelower threshold over time. Furthermore, in the body the impedance of thesystem is not only dictated by the reaction potentials across theelectrode-body interfaces but also by the impedance of the body tissueitself and the voltage drop that occurs through the tissue. The tissueimpedance may change due to capsule formation (e.g., fibrosis) aroundthe electrodes, movement, weight gain or loss, or other factors thatcause the body impedance to vary (increase or decrease) over time. Atlow frequencies because the driving voltage comprises the voltage dropacross the lead immediately surrounding tissue (ΔV_(lead)) and the body(ΔV_(body)) as shown below:V _(driving) =ΔV _(lead) ΔV _(body) =I*(R _(lead) +R _(body))

It can be advantageous in some cases to ensure that the voltage dropacross the lead does not exceed the safety threshold, because thatvoltage drop is dictated by electrochemical reactions. If one cancalculate the body resistance (R_(body)), then ΔV_(body) can bedetermined for a set current value (I) and the voltage drop across thelead (ΔV_(lead)) can be calculated and adjusted by adjusting the drivingvoltage (V_(driving)) to ensure that ΔV_(lead) remains in a safe range.

In FIG. 38 the electrode and body can be modeled as a resistor(R_(lead)) and capacitor (C_(lead)) in parallel and a body impedance(R_(body)) in series with the electrode. At low driving frequencies, theelectrode and body can be modeled as shown in FIG. 39 reflective of theequation above. At high driving frequencies the system can be modeled asshown in FIG. 40 where the capacitor behaves like a short and does nothave any impedance. Referring to FIG. 40 in this scenario, the systemcan be defined by the following equation where ΔV_(lead)=0 becauseR_(lead)=0:V _(driving) =ΔV _(lead) ΔV _(body) =I*(R _(lead) +R _(body))=I*R_(body)

By knowing V_(driving) and the current (I), the body impedance(R_(body)) can be calculated:R _(body) =V _(driving) /I

Therefore, the lead or electrode voltage drop can be calculated (e.g.,via a processor) and controlled by adjusting the overall drivingvoltage:ΔV _(lead) =V _(driving) −ΔV _(body)

This can allow the system to maintain the voltage below a set threshold.ΔV _(lead) <V _(threshold)

Referring again to FIG. 40 the ability to simulate the short across thelead or electrode-body interface can be implemented by generating ashort current input as seen circled in the figure. In some embodiments,the current input include a current amplitude on the order of up toabout 10 microseconds, from about 10 to about 20 microseconds, fromabout 20 to about 50 microseconds, from about 50 to about 100microseconds, from about 100 microseconds to about 200 microseconds,more than about 200 microseconds, or ranges including any two of theaforementioned values. This current input can occur at the beginning ofthe DC cycle, during the DC cycle, or after the DC cycle in order todetermine the body impedance to allow for adjustment of the drivingvoltage in order to maintain the lead or electrode voltage below a setthreshold. The set threshold may be a safety threshold such as theelectrolysis potential. The current input may be performed each cycle orevery other cycle or periodically or on demand as desired to allow fordetermination of the lead or electrode voltage drop. This voltage dropknowledge can then be used to adjust the driving voltage in an automatedcontrol loop or manually. After the initial high frequency currentinput, the DC current waveform may be applied based on the adjusteddriving voltage as determined in the prior high frequency current input.

If the lead or electrode voltage is determined to be in excess of athreshold value it can also be adjusted by adjusting the deliveredcurrent by reducing the current amplitude as shown in FIG. 41 whereinthe portion of the waveform where the threshold is reached, the currentis reduced to stay below the threshold. In a silver-silver chlorideelectrode application with both as the counter electrode and the workingelectrodes, controllers implementing the algorithm described canadvantageously enable self-balancing of charge. The silver-silverchloride system can exhibit higher voltages during the anodic phase(positive voltage) for the working electrode when the amount ofavailable AgCl on the corresponding counter electrode partially depletessuch that less easily reacted AgCl leads to higher potentials to drivethe reaction. By reducing the amount of charge pulled from the counterelectrode during the anodic phase (open arrows) but having a fullamplitude current during the cathodic phase (solid arrow), net charge isadded to the counter electrode helping to rebalance the chargedistribution between the electrodes.

It should be noted that the systems and algorithms described above canalso be used to maintain voltages within specific target driving voltageand lead voltage ranges as desired and set by the end user within thealgorithm.

FIGS. 42A-C show schematically an embodiment of an electrode lead 2100configured to deliver ionic direct current to tissue in proximity to thelead 2100. The lead 2100 can include a portion 2104 through which ioniccurrent can pass into the tissue and an electrically insulated portion2102. The portion 2104 through which ionic current can pass is inproximity to an ionic current generation source 2112. The system furthercan comprise an electric current connection 2103 to a power source. Thecurrent source may be located external or internal to the body dependingon the application need. Some embodiments comprise an ionic currentgeneration source comprising a silver cylindrical ring with a silverchloride layer on its exterior surface as generated by techniques suchas by oxidizing silver in a saline solution. An electrical connectionbetween the silver and power source is facilitated by electricallyconnecting a conductive conduit such as a wire to the silver cylindricalring such as by welding, mechanical fusing or other techniques known inthe art. As shown in the cross-sectional views FIG. 42B (cross sectionthrough the insulated portion) and FIG. 42C (cross section through theionically conductive portion), this electrical connector 2108 may bepreferentially situated in the interior of the silver cylindrical ringand within the external diameter of the insulated portion 2106 of thelead 2100. The insulated portion 2106 of the lead 2100 is molded aroundthe silver/silver chloride ring and electrical connector 2108 comprisingan electrically insulating material such as silicone or polyurethane.Additionally shown in FIG. 42C is ionic current generator 2112 andelectrical connection to the ionic current generator 2110. A moldingprocess leaves the cylindrical outer surface exposed. Another embodimentcomprises a silver ring with external diameter in the range of about 1.0to 1.5 mm with wall thickness of about 0.08-0.14 mm. In the embodimentdescribed above, ionic current in the form of chloride ions may begenerated by driving a cathodic current through the silver chloride toconvert the silver chloride to silver that is redeposited on the silvercylindrical ring and free chloride ions. The end of the lead may also beblunt or tapered or rounded to facilitate improved insertion andnavigation through the body. In other embodiments, the silvercylindrical ring may be replaced by alternative substrates includingplatinum, stainless steel, titanium, gold, platinum-iridium. To increasethe available electrochemical surface area (ESA), the substrate maycomprise microstructural features that increase the available surfacearea. In some embodiments, the substrate may comprise an open porositysintered component. In some embodiments, the substrate may comprise anopen porosity foam component such as a reticulate foam structure. Insome embodiments, the substrate may comprise surface texturing frommicromachining to generate features such as grooves or roughness toincrease the overall ESA. These micromachining tools may comprise laserablation to generate channels or grooves or general surface roughness.Additional micromachining techniques which can accomplish these goalsare electric discharge machining (EDM), material etching techniques,pattern masking and etching techniques, bead or grit blasting, andsurface sanding. The alternative substrate ring material may further becoated with a high charge capacity material such as sputtered iridiumoxide (SIROF), Poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate)(PEDOT), titanium nitride (TiN), fractal titanium nitride, poroustitanium nitride, or some combination thereof.

FIGS. 43A-43D show an embodiment of an electrode lead 2300 configured todeliver ionic direct current to tissue in proximity to the lead similarto FIGS. 42A-42C in which the lead has been covered in an ionicallyconductive medium 2314 to facilitate transmission of ionic current fromthe ionic current generator 2312 to the target tissue. As shown in FIG.43A, the electrode lead 2300 includes an insulated portion 2302,ionically conductive portion 2304, and a portion 2303 operably connectedto a power source (not shown). FIG. 43B is a cross-section through theinsulated portion 2302 of FIG. 43A illustrating electrical connector2308 within insulator 2306. FIG. 43C is a cross-section through theionically conductive portion 2304 of FIG. 43A illustrating electricalconnector 2308 within insulator 2306, as well as ionic current generator2312, ionically conductive medium 2314, ionically selective membrane2316, and electrical connection 2301 to the ionic current generator2312. The ionically selective membrane 2316 is shown to enable passageof ions but limiting passage of other materials through the membrane. Insome embodiments the ionically conductive medium 2314 and ionicallyselective membrane 2316 are restricted to the ionic current generator2312 portion of the lead 2300, as shown in the longitudinalcross-section of FIG. 43D. In some embodiments, the ionically conductivemedium 2314 comprises a high salt content hydrogel with an anionexchange membrane as the ionically selective membrane 2316 allowstransmission of anions, e.g., chloride ions, but limits transmission ofcations and uncharged particles.

FIGS. 44A-44C illustrate another embodiment of an electrode lead whereinthe ionically conductive medium 2314 in FIG. 43A-43D is absent, andinstead the ionically selective membrane 2316 is in direct contact withthe ionic current generator 2312 and insulator 2306 exterior surface.FIG. 44B is a cross-section through the insulated portion 2302 of FIG.44A illustrating electrical connector 2308 within insulator 2306. FIG.44C is a cross-section through the ionically conductive portion 2304 ofFIG. 44A. In some embodiments the ionically selective membrane 2316 islocalized only to the ionic current generator 2312 portion of the lead2400. In other embodiments the membrane 2316 covers both the ionicallyconductive portion 2304 and the insulated portion 2306 of the lead 2400.In some embodiments, the ionically selective membrane 2316 comprises ananion exchange membrane. This membrane 2316 can be formed on the lead2400 in a variety of ways including dip-coating the lead 2400 in a bathof solvated anion exchange membrane ionomer and driving off the solventby heating or another chemical process to yield the final coating on thelead. The coating may be preferentially bonded to the insulated portionof the lead. The coating may also be configured to have gas permeableproperties such as if gaseous species are generated below the coating,the gas can escape or dissolve into the surrounding tissue and beevacuated by the body. In another embodiment small channels in thecoating are present to enable any gas formed below the coating to ventand escape from the region between the coating and the electrodesurface.

FIGS. 45A-45C show an embodiment of an electrode lead 2500 configured todeliver ionic direct current to tissue in proximity to the lead. Asillustrated in FIG. 45A, the lead 2500 comprises a portion 2304 throughwhich ionic current can pass into the tissue and an electricallyinsulated portion 2302 as previously described. The electrode lead 2500also comprises a reference electrode 2505 used to provide arepresentative measurement of the potential difference across theionically conductive portion 2304 of the lead 2300 and the immediatelyadjacent tissue. In this embodiment an ionically selective membrane 2316is situated over the lead 2500 and is preferentially an anion exchangemembrane. A direct measurement between the ionically conductive portion2304 of the lead 2500 and the distal counterelectrode would be lessaccurate due to current flow between the two electrodes leading to ohmicpotential drops that can obscure the true potential difference as wellas the potential drop due to body resistance between the working andcounterelectrodes. The reference electrode 2505 can be configured to bea high-impedance electrode which limits current flow through theelectrode limiting potential difference measurements from being skeweddue to ohmic potential drops across the electrode-environment interface.In one embodiment the reference electrode 2505 comprises a silvercylindrical ring with a silver chloride coating on its exterior surface.In an alternative embodiment the reference electrode 2505 may be madefrom a platinum or platinum-iridium alloy. FIG. 45B is a cross-sectionthrough the insulated portion 2302 of FIG. 45A illustrating electricalconnector 2308 within insulator 2306. FIG. 45C is a cross-sectionthrough the ionically conductive portion 2304 of FIG. 44A.

FIG. 46 shows an alternative embodiment to FIGS. 45A-45C in which anelectrode lead 2600 comprises a portion 2304 through which ionic currentcan pass into the tissue, and an electrically insulated portion 2302.The electrode lead also comprises a reference electrode 2505 aspreviously described and used to provide a representative measurement ofthe potential difference across the electrochemically active portion ofthe ionically conductive portion 2304 of the lead 2600 and immediatelysurrounding tissues. The reference electrode 2505 is located inproximity to the ionically conductive portion 2304 of the lead 2600 butremains electrically isolated and spaced apart from the ionicallyconductive portion 2304 of the lead 2600.

FIG. 47 shows an embodiment of an electrode lead 2700 comprising aconnector 2703 for the connection to an electrical power source (notshown), an insulated portion of the lead 2702 and multiple spaced-apartionically conductive portions 2702 of the lead along with an ionicallyselective membrane 2716 or coating applied over the ionically conductiveportions 2702 of the lead. The multiple ionically conductive contacts2702 may be operated independently, in pairs, or in alternating patternsto deliver current to the proximal tissue. Furthermore, the contacts maybe operated not only in a current delivery mode but may be run in a highimpedance mode as reference electrodes to measure the potentialdifference between the working electrodes (ionically conductive portionspassing current) and the counter electrode which can be the body of thepower supply unit. In some embodiments, the working electrodes may beconfigured such that they deliver different ionic DC levels to optimizethe nerve block desired. Some embodiments can include about or at leastabout 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 25, 32 ormore ionically conductive portions, or ranges including any two of theaforementioned values.

FIG. 48 shows that in a rat model, a stimulation force of thegastrocnemius muscle due to stimulation of the sciatic nerve can betuned such that the nerve is unblocked (0%) or fully blocked (100%) ortuned to a partial block between 0% and 100%, such as about 10%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, or ranges including any two of theaforementioned values. As seen, increasing the DC block amplitudedecreases the stimulation force in a gradual manner so that this nerveblock tuning and current field tuning is possible similar to what isperformed with current spinal cord stimulators that use AC stimulationsignals.

FIG. 49 shows an embodiment of a multi-contact electrode lead 2900configured to deliver ionic direct current to tissue in proximity to thelead 2900. The lead 2900 comprises a plurality of contacts 2304 throughwhich ionic current can pass into the tissue and an electricallyinsulated portion 2302. The electrode lead 2900 can also comprise areference electrode or electrodes 2505 used to provide a representativemeasurement of the potential difference between the ionically conductiveportion of the lead 2900 and immediately adjacent tissue as previouslydescribed. By having a relatively high-density configuration ofionically conductive contacts 2304, the current field as referenced inFIG. 48 can be configured and customized with high level of precision byindividually addressing and controlling the contacts. Furthermore, areference electrode or multitude of electrodes can help ensure that theelectrochemical reaction of the ionically conductive contacts operatewithin the desired operating parameters.

FIGS. 50A-50B illustrate an alternate configuration of a curvedmulti-contact electrode lead 3000 configured to deliver ionic directcurrent to tissue in proximity to the lead. FIG. 50A is a side view, andFIG. 50B is a perspective view. The system can be designed to be wrappedaround a nerve as a nerve cuff 2306 and may have a plurality of ioniccurrent conductive contacts 3005 along the length of the nerve cuff 2306as illustrated. The long axis of the electrode can run substantiallyperpendicular to the long axis of the nerve which is captured in theinterior portion of the curved aspect of the electrode. Alternatively orin combination, the cuff 2306 may extend along the length of the nerveand had discrete contacts that run along the width of the cuff 2306(running along the length of the nerve). The contacts may be usedindependently or together to generate ionic DC block. Contacts 3005 mayalso be used as reference electrodes in some embodiments.

As shown in FIG. 51 the ionic current generation portion 3100 of theelectrode may be generalized to having a conversion mechanism fromelectrical current supplied by the electrical connection 3106 to anelectrochemical system (3101 and 3102) which convert the electricalcurrent into ionic current. The electrochemical system may be optionallycovered with an ionically selective membrane or ionically conductivemedium 3103 to facilitate transport of the ions from the ion generationsystem to nearby tissues. The surface of the ion generation system 3100may also include a recessed surface 3105 relative to adjacent insulatingsurfaces 3104 to generate a more even current field profile along theionically conductive electrode surface to facilitate even ion generationalong the electrode. In some embodiments, the ion generation system 3100comprises a substrate made of silver 3101 with a primary coating ofsilver chloride 3102 adhered to the exterior surface of the substrate3101. An anion exchange membrane can be optionally adhered to thesurface of the electrode and insulator to enable chloride ions to passbut to prevent cations and uncharged particles from passing through thecoating 3103. In other embodiments, the substrate 3101 may comprisealternative substrates including platinum, stainless steel, titanium,gold, platinum-iridium. To increase the available electrochemicalsurface area (ESA), the substrate may comprise microstructural featuresthat increase the available surface area. In some embodiments, thesubstrate may comprise an open porosity sintered component. In someembodiments, the substrate may comprise an open porosity foam componentsuch as a reticulate foam structure. In some embodiments, the substratemay comprise surface texturing from micromachining to generate featuressuch as grooves or roughness to increase the overall ESA. Thesemicromachining tools may comprise laser ablation to generate channels orgrooves or general surface roughness. Additional micromachiningtechniques which can accomplish these goals are electric dischargemachining (EDM), material etching techniques, pattern masking andetching techniques, bead or grit blasting, and surface sanding. Thesubstrate 3101 may further be coated with a coating 3102 such as highcharge capacity material such as sputtered iridium oxide (SIROF),Poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT),titanium nitride (TiN), fractal titanium nitride, porous titaniumnitride, or some combination thereof. In some embodiments, the primarycoating 3101 may comprise an adhesion layer to promote adhesion betweenthe substrate 3101 and the secondary coating 3103. An exemplaryembodiment is deposition of a titanium adhesion layer 3101 to promoteadhesion of a secondary coating 3103 of titanium nitride to differentsubstrate 3101 surfaces.

FIG. 52 illustrates how an ionically conductive portion of the electrodecan be configured to generate a more even current density profile alongthe width 3206 of the electrode. As shown in the graph, recessing thesurface 3210 of the conductive electrode 3204 at a depth 3208 in betweeninsulated portions 3202 can help make the current density of the edgesof the electrode approach that of the center of the electrode. Thecurrent generating surface 3210 may also be configured to be coveredwith one or more coatings as previously described that enable transportof ions such as an ion exchange membrane but restrict passage of otherparticles.

FIGS. 53A-53D illustrates one embodiment of an ionic direct currentelectrode lead 3300 with paired ionic current generation contacts 3302,which can be silver contacts (or titanium nitride, or other materialincluding those disclosed elsewhere herein), that can be adhered using ahelical wire form 3304, which can be made of silver. FIG. 53Aillustrates an exploded view of various components of the ionic directcurrent electrode lead 3300, including ionic current generation contacts3302, helical wire form 3304, insulated wire 3306, and end of insulatedwire 3308. As shown in FIG. 53B, the helical wire form 3304 is shownconnecting the current generation contacts 3302 along the interioraspect of the ionic current generation contacts 3302. The helicalwireform 3304 may be fused or placed in electrical contact with thecurrent generation contacts 3302 via laser welding, spot welding,physical contact, ultrasonic welding or other means of providingelectrical contact between the two objects, as shown in FIG. 53D alongfixation points 3310. As shown in FIG. 53C a lead contact assembly crosssection, an insulated wire 3306, which can be a 16 strands PTFE coatedlead, is then connected electrically to the helical wireform 3304. Theend of the insulated wire 3308 is stripped such as by laser ablation toexpose the conductive core and may comprise a solid core ormultistranded configuration. The laser ablated section may be a varietyof sizes, such as 0.15-0.25 mm or other suitable sizes such as less than0.15 mm or greater than 0.25 mm. The insulated wire 3306 can comprise avariety of configurations, which can include at least 16-22 strands ofMP35 or Med. SS 0.1 mm overall diameter. The insulated wire 3306 cancomprise a coating of different thicknesses and materials, which can atleast include PTFE coatings of 15-20 microns thick. The exposedconductive aspect 3308 of the wire 3306 can then be crimped and/or fusedto the helical wire form 3304 to create an electrode pair unit. It canbe appreciated that the number of connected current generation contacts3302 may be fewer or greater than that shown for each helical wire form3304.

For example, each helical wire form may have a single current generationcontact in electrical contact with it and an associated insulated wireto provide electrical connectivity to the electric power supply. Thecurrent generation contact may be configured to have electrochemicalproperties such that when provided with electrical current, a portion ofthe contact can transform that electrical current into ionic current. Inone embodiment the current generation contact comprises a silvercylindrical body with silver chloride on the outer cylindrical surfaceof the contact that can release chloride ions when driven with acathodic current. These lead contact constructions of ionic currentgenerating contacts, helical wire form, and insulated wire may becombined to generate electrodes with multiple leads that can be space inproximity with an even spacing or uneven spacing as desired for thespecific application. Specific lead contacts may be used as workingelectrodes to generate ionic current or reference electrodes to measurethe potential difference between the electrode lead and a counterelectrode or between the electrode lead and immediately adjacent tissueor may be used as both by switching them between different states. Theplurality of lead contacts may then be positioned and physicallyconnected by a binding material that can be molded around and throughthe lead contacts to create an elongated lead structure. This bindingmaterial may be a flexible polymer and is preferentially biocompatible.Example materials include silicone and polyurethanes. This bindingmaterial may preferentially be an electrical insulator. This bindingmaterial in preferentially insulating to ionic current. A coating mayfurther be situated around the electrode lead to allow passage of ionsfrom the electrode into the target tissue. The coating may comprise ananion exchange membrane which allows anions such as chloride ions topass through from the ionic current generation portion to tissue inproximity to the lead.

FIG. 54A illustrates a lead sub-assembly 3400 (top) and a lead with oneor a plurality of contacts 3402 as previously described in connectionwith FIGS. 53A-53D above. The contacts 3402 can allow for ionic currentgeneration as previously described. FIG. 54B illustrates a plurality ofcontacts 3402 coupled to a plurality of ends of insulated wires 3308.

FIGS. 55A-55D illustrate further views of electrode leads. The leadcontacts 3402 can be connected by a binding material 3420, and/or have acoating 3422 as noted elsewhere herein. The system can be designed todesignate particular working as well as reference electrodes. FIG. 55Billustrates a binding material 3420, which can be a silicone overmoldhaving the shape depicted, prepared to connect and/or cover the leadcontacts 3402, and FIG. 55A illustrates the binding material 3420applied to the lead contacts 3402. FIG. 55D illustrates the coating3422, which can be an ion exchange coating, prepared to coat the leadcontracts 3402, and FIG. 55C illustrates the coating 3422 coating thelead contacts 3402.

FIGS. 56A-56C schematically illustrate a generally tubular, e.g.,cylindrical lead contact 3402 that can include a sidewall with distalnotches 3403 and an interior lumen. One, two, or more conduits 3404 canbe housed at least partially within each lead contact 3402 withconductive end portions 3405 in electrical communication with the leadcontact 3402. As illustrated in FIG. 56B, the conductive end portion3405 can be positioned, which can include retained, within the distalnotch 3403. As shown in FIG. 56C, a plurality of conduits 3404 can begrouped together with each having a conduct end portion 3405 extendingoutward.

FIGS. 57A-57B schematically illustrate additional lead embodiments,illustrating conduits and spaced-apart lead contacts as previouslydescribed. FIG. 57A illustrates contacts 3402 without binding materialor a coating layer, while FIG. 57B illustrates contacts connected with abinding material 3420 which may, for example, comprise silicone that hasbeen overmolded onto and throughout the other components except whereexcluded such as along the outer electrode contact surfaces. Optionallya coating layer 3422 may be situated as a surface layer over the leadembodiment as shown in FIG. 57C. In some embodiments this coating layermay comprise an ionically conductive polymer such as an anion exchangemembrane.

FIGS. 58A-58D illustrates embodiments of lead electrodes having paddleconfigurations. The electrodes could include an ionic current generationelement (e.g., Ag/AgCl) generally in electrical continuity along thepaddle that can include a serpentine shape as shown in FIG. 58B, oranother shape. The paddle could have an ionically permeable covering onboth sides as shown in FIG. 58A, an ionically permeable covering on oneside only as shown in FIG. 58D, or an ionically impermeable covering onat least one side as shown in FIG. 58C.

FIG. 59 illustrates an embodiment of a cylindrical lead 1600, that caninclude a fluid conduit 162 configured for filling of an enclosed volumewith ionically conductive medium including saline, electrolyte, gels,etc. Also illustrated is a proximal connector and endcap 1604, that canallow for connection to the proximal end of the system, and can allowfor electrical contact to the interior coiled electrode 1606.

FIG. 60 illustrates a clinical treatment flowchart algorithm in whichthe lead is placed into a desired target anatomical location, e.g., theepidural space 6002 and positioned along the spinal cord 6004 andinserted to the desired spinal column level 6006. Subsequently, the leadcan be connected to a power supply whether for permanent implant orexternal use and initiation of ionic direct current generation can begin6008. In some instances the spinal cord region being accessed is theanterolateral aspect of the cord including the region closest to thespinothalamic tract. In some instances the positioning comprisespositioning the lead or leads along the dorsal aspect of the spinalcolumn. Once the lead or leads have been positioned in the appropriatelocations, ionic direct current can be generated to initiate block ofthe nerve tissue proximal to the ionic current generating contacts.Current generation may lead to a constant block or intermittent block ofthe nerve tissue. In some clinical treatment algorithms the nerve tissueis dosed with ionic direct current for a period of time and then stoppedsuch that the residual pain is significantly lower than the initial paineven without active nerve block, such that the device can provide areduced or pain free treatment-free period or holiday.

FIG. 61 illustrates a clinical treatment flowchart algorithm in whichthe lead is placed into the body 6102 and ionic current generatingcontacts of the lead are positioned along a target nerve (orperipherally in other embodiments) for nerve block 6104. Subsequently,the lead can be connected to a power supply whether for permanentimplant or external use and initiation of ionic current generation canbegin 6106. Once the lead or leads have been positioned in theappropriate locations, ionic direct current can be generated to initiateblock of the nerve tissue proximal to the ionic current generatingcontacts. Current generation may lead to a constant block orintermittent block of the nerve tissue. In some clinical treatmentalgorithms the nerve tissue is dosed with ionic direct current for aperiod of time and then stopped such that the residual pain issignificantly lower than the initial pain even without active nerveblock, such that the device can provide a reduced or pain freetreatment-free period or holiday.

FIG. 62 illustrates a clinical treatment flowchart algorithm in whichthe body space is accessed 6202, and ionic current delivery leadcontacts are positioned within the body proximate target nerve tissue6204. The lead can then be positioned to a precise target location 6206as needed. The lead may then be put into a sensing mode to measureactivity along the target nerve 6208. The lead can then be connected toa power source, and/or the connected power source activated. Onceundesired nerve activity is detected, the system can initiate ionicdirect current generation to reduce activity of the nerve or completelyblock the nerve signal 6210. In some embodiments, the system continuesto sense activity on the nerve for example by using a contact positioneddistal to the central nervous system direction to see if undesiredactivity is still being transmitted along the nerve. Once the systemdetermines that the nerve activity is falls below a target threshold6212, the ionic current may be modulated and reduced 6214. Acomplementary sensing configuration involves the system described abovebut also incorporates a contact positioned proximal to the centralnervous system direction to monitor transmission of the undesired signalthrough the nerve tissue. The direct current may be modulated to bringthe transmitted signal sensed by the proximal contact below a targetthreshold. This feedback can provide a means for creatingpatient-specific therapeutic thresholds by taking in patient inputs todetermine these initial target thresholds. By applying machine learningalgorithms, the system can improve its ability to recognize undesirednerve activity that requires blocking (partial or complete) fromactivity that does not lead to the undesired sensations experienced bythe patient. Over time by monitoring patterns in undesired nerveactivity, blocking current delivery, and proximal signal transmission,the system may be better able to anticipate and more quickly orautomatically address undesired nerve activity.

FIG. 63 illustrates an embodiment of an electrode lead system 6300operated in continuous block mode, where dual ionic direct currentgenerating electrodes 2304, 2305 interface with a nerve but are drivenfrom a current source via electrically insulated leads 2302 withcurrents of opposite polarities such that when one is in a blockingphase, the other is in a non-blocking phase which resets the electrodefor blocking once the current polarity is again reversed. With thisconfiguration, a constant block can be advantageously maintained alongthe nerve. The electrodes may be oriented as shown in series along anerve or oriented on opposite sides to the nerve tissue itself.

FIGS. 64A-64H illustrate various embodiments of separated interfacenerve (SINE) electrodes. FIG. 64A illustrates an embodiment of a SINEelectrode 700 that can include a casing 702, which can be disc-shapedand hermetically sealed in some embodiments. Also shown is a stimulationelectrode 704 configured to drive charge generation in electrodes togenerate ionic current. The current can also be reversed to generate awaveform. A reference electrode 706 is also illustrated, that can allowfor measurement of potential drop across an electrode interface. Thereference electrode 706 could include silver/silver-chloride, orplatinum. Also illustrated is an ion conduit 708 that can be filled withion transmissive material, such as saline, an electrolyte, or anionically conducting gel or polymer. An electrode contact region 710 isalso illustrated with a distal end and/or a sidewall port. A microporousfilter, ionically transmissive material, and ionic exchange membrane arealso illustrated. FIGS. 64B through 64D illustrate non-limitingadditional features of the disc-shaped casing, any number of which canbe utilized in some embodiments. FIG. 64B illustrates a casing 702 in aassembled configuration, while FIG. 64C illustrates the casing 702 in anunassembled configuration. As shown in FIG. 64C, the casing 702 has analignment feature 712 that is configured to interface with acorresponding alignment opening 716 in an electrode stack 714, shown inFIG. 64D, configured to generate charge and ionic current. FIG. 64Dfurther illustrates a fluid conduit to electrode contact region 718 atwhich the ion conduit interfaces with the electrode stack 714. Theelectrode stack 714 has disks or electrode surface(s) 720, which can bemetal plates that are configured to generate charge, and a disk(s) orspacer(s) 722 that is configured to hold fluid for ion conduction andcontact an electrode. The electrode surface(s) 720 can be perforated toenable fluid and ion flowing through the electrode surfaces(s) 720 andbetween the spacer(s) 722. The electrode surface(s) 720 can be made of avariety of materials, such as titanium, titanium coated in titaniumnitride, titanium with sputtered iridium oxide film (SIROF), and/orothers. The electrode surface(s) 720 can include a substrate of 304 or316 stainless steel, platinum or titanium nitride coated Pt, SIROFcoated Pt, and/or PEDOT coated Pt. The spacer(s) 722 can be made of avariety of materials, which can include porous or fluid passing polymeror nonconductive material, polyester, nylon, PEEK, polycarbonate, and/orothers. The material of the spacer(s) 722 can be knitted, non-woven,meshed, perforated, and/or other configurations.

FIG. 64E describes embodiments of disks or electrode surfaces 720, withnon-limiting example dimensions in millimeters of various features, thatcan be made of titanium material and perforated, and configured to bepositioned within the disc-shaped casing. Base geometry example of thetextured region of the disk 720 is a 0.1 or 0.13 mm thick grade 2titanium foil/sheet. FIG. 64F describes embodiments of disks or spacers722, with non-limiting example dimensions in millimeters of variousfeatures, that can be made of a polymer material such as a 0.2 mm thickpolyester woven like Dacron, and configured to be positioned within thedisc-shaped casing. Other materials can also be used. FIG. 64Gillustrates embodiments of the SINE electrode 700 and, moreparticularly, features of the fluid conduit 724, that can be filled withan ionically conductive medium such as saline, electrolyte, and/or agel, as well as a reference electrode 706. FIG. 64H illustrates anotherembodiment of a SINE electrode 750 that can include a generallycylindrical geometry, coiled electrode surface 752, fluid retentionspacer 754, insulating conduit 756, and electrode contact region 756.The coiled electrode surface 752 can include characteristics that arethe same or similar to the disks or electrode surface(s) 720. The fluidretention spacer 754 can be configured to be ionically conductive. Thefluid retention spacer 754 can enable filing of an enclosed volume withionically conductive medium (such as saline, electrolyte, etc.) suchthat the fluid is held in proximity to the coiled electrode surface 752to enable electrochemical reactions to occur. The fluid retention spacer754 can physically retained an electrode centered and positioned. Thefluid retention spacer 754 can include cylindrical felt, poroushydrophilic polymer material, ionically conductive gel, and/or othersuitable materials. The electrode contact region 758 can be positionedon a distal end, or side port, of the SINE electrode 750. The electrodecontact region 758 can include a microporous filter or frit, anionically transmissive material, and/or ion exchange membrane.

FIGS. 65A-65D illustrate embodiments of high charge density electrodesand electrode leads. As shown in FIG. 65A, increasing thecharge-carrying surface area via surface area multiplication technologycan advantageously and surprisingly increase the efficacy of the highcharge density electrodes and leads. For example, the lead 800, whichcan be an electrode, can have a microstructure 802A, which can include aplurality of plate-like structures. The microstructure 802A can includesurface characteristics 804A that increase the surface area of themicrostructure 804A. Other microstructures and/or surface treatmenttechnologies can be used to increase surface area. The high chargedensity electrodes and leads can be made of a variety of materials,which can include solder thermal interface materials (STIM) and/orimplant-compatible materials. FIG. 65B illustrates non-limiting examplesof high charge density materials and associated characteristics that canbe utilized in some embodiments. FIG. 65C illustrates non-limitingexamples of surface area multiplication technology techniques. Forexample, sintering, packed filament (e.g. wire/(“fuzz button”)/“steelwool”), laser patterning/etching, micromachining, foaming, and/or othertechniques may be used at a microscale. An example of micromachining isshown with microstructure 802A. An example of laser texturing with pulsetechnologies is shown with microstructure 802B. An example of metallicfoam trabeculae is shown with microstructure 802C. An example of packedfilament (e.g. wire/“fuzz button”/“steel wool”) is shown withmicrostructure 802D. Surface treatments alone or with themicrostructures detailed above can be used to increase surface area. Forexample, fractal deposition shown with surface 804A can increase surfacearea, which may include TiN. Surface activation is another surfacetreatment that can increase surface area, which may include IrOx. Insome embodiments, creating a microstructure within the high chargedensity substrate material to increase an available electrochemicalsurface area of the high charge density substrate material can increasethe available electrochemical surface area by about or at least about2×, 3×, 4×, 5×, 6×, 7×, 8×, 9×, 10×, 15×, 20×, 25×, or more or rangesincluding any two of the foregoing values.

FIGS. 65D-65E illustrate embodiments of a surface area multiplicationtechnology technique that can include texturing of a rod and/or tube. Atarget rod or tube can have a variety of diameters which can include 1.5mm or other suitable diameters such as less than 1, 1-1.25, 1.25-1.5,1.5-1.75, 1.75-2, or greater than 2 mm, or ranges including any two ofthe foregoing values. The textured region on a target rod or tube can bea variety of lengths, which can include 3.5-4 mm or other suitablediameters such as less than 3, 3-3.5, 3.5-4, 4-4.5, 4.5-5, or greaterthan 5 mm. The inner diameter of a target tube can be a variety ofsizes, which can include 1-1.1 mm or other suitable inner diameters suchas less than 0.8, 0.8-0.9, 0.9-1, 1.1-1.2, 1.2-1.3, 1.3-1.4, 1.4-1.5, orgreater than 1.5 mm. The rod can be made of a variety of stockmaterials, which can include Grade 2 Ti solid rod with an outer diameterof 0.0625″ and length of 12.″ The tube can be made of a variety of stockmaterials, which can include as one non-limiting example SS316HypoTubing, 17 Gauge, 0.058″ outer diameter, 0.042″ inner diameter,0.008″ wall, and 12″ length.

FIG. 65D illustrates a rod or tube 800 that is textured to increasesurface area. The rod or tube 800 can include a plurality of channels806. The plurality of channels 806 can be circumferential and/or spiral(including having multiple parallel spirals). In some aspects, theplurality of channels 806 may include channels that run perpendicular tothe circumferential direction of the tube or rod 800 that createtexture. Each of the plurality of channels 806 can be spaced apart by“a” microns or micrometers, have a channel width of “b” microns ormicrometers, and have a channel depth of “c” microns or micrometers. Thechannel can have varying aspect ratios where a, b, and c have differentvalues. For example, {a, b, c} can equal {25, 25, 25}, {25, 25, 50},{25, 25, 75}, {25, 25, 100}, {50, 50, 50}, {50, 50, 100}, {50, 50, 150},{50, 100, 150}, {100, 100, 100}, {100, 100, 150}, or other suitablecombinations.

FIG. 65E illustrates an embodiment of a rod 800A and tube 800B withtexturing. The rod 800A includes a textured region 808A. In someaspects, the textured region 808A is 3.5 mm in length and is positioned4-5 mm from a first end 810 of the rod 800A but other sizes can beimplemented. The rod 800A can be a length of 25 mm and have a diameterof about 1.5 mm but other sizes can be implemented. The tube 800B has atextured region 808B covering the entire outer periphery. In someaspects, the textured region 808B covers a portion of the outerperiphery. The tube 800B and textured region 808B are both 3.5 mm butother sizes can be implemented, including when the length of the tube800B and the textured region 808B are not the same length. The tube 800Bcan have an outer diameter of about 1.5 mm but other sizes can beimplemented.

FIG. 65F illustrates an embodiment of a surface area multiplicationtechnology technique that can involve laser texturing of a titaniumfoil/sheet. The base geometry of the Ti foil/sheet can be, in someembodiments, a 0.1-0.2 mm thick Grade 2 Ti foil/sheet or other suitablethicknesses such as less than 0.1 mm or greater than 0.2 mm. A varietyof stock materials can be used for the Ti foil/sheet, which can includeGrade 2 Ti/foil that is 0.13 mm, 0.1 mm, or other suitable thicknesses.

FIGS. 65G-65K illustrate that the cathodic charge storage capacity(shaded regions) can be measured using cyclic voltammetry by sweepingthe voltage across the electrode interface for that material's waterwindow or voltage range within which electrolysis will not occur to seehow much charge can be generated by the material without generatingdeleterious by-products that can be harmful to surrounding tissue duringin vivo use. For a given material type and surface area and voltagesweep rate the charge storage capacity can be measured. For example, asshown in FIG. 65H, the charge storage capacity of titanium (Ti) over the−0.6 to 0.8 voltage range is 1.3 mC/cm². Notably, even for a givenmaterial, its particular form and structure can be important fordictating its charge storage and charge injection capacity. For example,as seen in FIG. 65I comparing titanium (Ti) and smooth titanium nitride(TiN) over the −0.6 to 0.8 voltage range, the charge storage capacity ofthe titanium (Ti) at 1.3 mC/cm² is greater than that of the smoothtitanium nitride (TiN) at 0.4 mC/cm². However, as seen in FIG. 65J whencomparing smooth titanium nitride (TiN) to “rough” porous titaniumnitride (TiN) at 13.8 mC/cm² the charge storage capacity increasessubstantially in large part due to the additional surface area availableon the porous titanium nitride (TiN). As highlighted in FIG. 65K, theimpact of material properties on charge storage capacity can be highlydependent on composition and preparation as the desired material, e.g.,sputtered iridium oxide film (SIROF) coated material shows very highcharge storage capacities at about 50 mC/cm² compared to titaniumnitride.

FIGS. 66A-66C schematically illustrate embodiments of various aspects ofmedical electrical delivery systems and components. FIG. 66Aschematically describes examples of electrode types that can be utilizedin combination with other embodiments described herein, including highcharge capacity material electrodes, separated interface nerveelectrodes, and silver/silver-chloride with polymer coatings. FIG. 66Bcompares examples of charge delivery properties of various electrodetypes, including high charge density (HCD), separated interface nerveelectrode (SINE), silver/silver-chloride (Ag—AgCl) with polymer coating,and SCS. FIG. 66C illustrates one embodiment of a percutaneoussilver/silver-chloride lead 812 and paddle silver/silver-chloride lead814. In some embodiments, a silver/silver-chloride electrode can includean ion (e.g., anion) exchange resin configured to sequester silverwithin the polymer itself.

FIGS. 67A-67C illustrate examples of a pulse generator waveform that canadvantageously assist in achieving full nerve block quickly withoutunwanted side effects. In some embodiments, having higher cathodicamplitude than anodic amplitude (e.g., disproportionate cathodic-anodicphase duty cycles) can potentially widen the therapeutic window fortherapy. By using a smoothed trapezoidal waveform with ramps up totarget anodic and cathodic current magnitudes, unwanted generation ofactivation potentials is avoided by more gradually increasing thecurrent and electric field compared to a more abrupt transition inelectric field potential as might be facilitated with a square wavewaveform. Furthermore, making the transitions from ramp region toplateau a smooth function with a continuous derivative ofD_(current)/D_(time) instead of an abrupt transition can furtherincrease the therapeutic range of the therapy prior to generatingunwanted activation potentials. The smoothing function may comprise acubic hermite spline or other continuous waveform with at least firstderivative continuity. In some embodiments the leading ramp rate islower than the trailing ramp rate with a leading ramp rate that may bein the range of, e.g., 1 to 2 times slower or 2 to 4 times slower or 5or more times slower than the trailing ramp rate. In other embodiments,the leading and trailing ramp rate may be the same or the trailing ramprate may be slower than the leading ramp rate. In some embodiments themagnitude of the leading ramp rate may be in the range of up to about0.1 milliamperes/s (mA/s) or about 0.1 to about 0.5 mA/s or about 0.5 toabout 1.0 mA/s or about 1.0 to about 3.0 mA/s or about 3.0 to about 5.0mA/s or about 5.0 mA/s and higher, or ranges incorporating any two ofthe foregoing values. In some embodiments the magnitude of the trailingramp rate may be in the range of about 0 to about 1 milliamperes/second(mA/s) or about 1.0 to about 2.0 mA/s or about 2.0 to about 5.0 mA/s orabout 5.0 to about 10.0 mA/s or about 10 to about 20 mA/s or 20 mA/s andhigher, or ranges incorporating any two of the foregoing values.Furthermore having a higher cathodic amplitude (Ca) than anodicamplitude (Aa) with a disproportionate cathodic<anodic phase duty cycles(Ct<At) where total charge (area under each respective curve) remainsbalanced can advantageously widen the therapeutic window for therapy.

In some embodiments, direct current (DC) delivery amplitudes for anytherapy disclosed herein could be, for example, in the range of about 0to about 0.5 mA, about 0.5 to about 1.5 mA and about 1.5 to about 2.5mA, or ranges incorporating any two of the foregoing values. In someembodiments, about 2.5 mA to about 5 mA and about 5 mA and above can beutilized both for anodic and cathodic current levels for block. Responsehas been seen, for example at about 0-1.5 mA range in animal studies aswell as paresthesia onset in peripheral human nerves at about 1.5 mA(cathodic and anodic) with complete block at about 2.5 mA and currentdelivery up to about 5.5 mA.

In some embodiments, direct current delivery to a patient can betargeted to any number of anatomical locations, including but notlimited to: the dorsal root ganglion; dorsal roots; dorsal columns;dorsal horn; Lissauer's tract; and/or the antero-lateral pain tracts. Insome embodiments, direct current delivery can be directed to aperipheral nerve, or other target locations as described elsewhereherein. Not to be limited by theory, in some embodiments DC delivery canpotently modulate small diameter fibers in the spinal cord anddepolarize spinal cord neurons. DC delivery may not necessarily besensitive to fiber size, and may have a wide therapeutic window. DCdelivery can be utilized for a wide variety of indications, includingbut not limited to cardiac mapping for arrhythmias, epilepsy, andmovement disorders, as well as a variety of other conditions disclosedelsewhere herein.

The systems and methods described in the figures above may be used togenerate DC nerve block. Depending on the specific direct currentapplication of nerve block, nerve suppression, or continued block afterremoval or stopping of the current may occur, and hypersuppression mayresult for continued nerve blockade in excess of one minute afterremoval of the DC source to delay nerve conduction recovery. The nerveblock and suppression may be generated in an intermittent or continuousmanner depending on the desired application. Means for continuous nerveblock have been described that provide for safe delivery of nerve blockvia ionic current utilizing multiple electrodes or sequenced electrodecontact activation enabling a means to modulate nerve conduction safelywithout necessitating complex mechanical systems. The system may befully or partially implantable, or completely non-implantable (e.g.,transcutaneous) with all tissue contacting materials biocompatible fortissue contact and implantation compatibility.

In some embodiments, systems and methods as disclosed herein can be usedor modified for use as part of alternating current stimulation systems,including but not limited to spinal cord stimulation (SCS) systems fortreatment of chronic pain, such as for example the SENZA system by NevroCorporation; the PRECISION systems including PRECISION PLUS andPRECISION SPECTRA by Boston Scientific Corporation, and the INTELLISsystem from Medtronic PLC. As one example, systems and methods asdisclosed herein can increase efficacy of an alternating currentdelivery system including delivering alternating current via anelectrode and electrode lead to a target tissue of a patient utilizing aDC-offset waveform generated by a pulse generator and facilitated by acontroller. The alternating frequency could be any desired frequency,including high frequency systems of about 10 kHz or higher, from about1.5 kHz to about 100 kHz, from about 1.5 kHz to about 50 kHz, from about3 kHz to about 20 kHz, from about 3 kHz to about 15 kHz, from about 5kHz to about 15 kHz, or from about 3 kHz to about 10 kHz, or otherranges incorporating any two of the aforementioned values. The electrodeand/or electrode lead can include one or more of: high density chargematerials, a SINE electrode, and/or a silver-silver chloride material.Such systems and methods can in some cases advantageously increase theexcitability of target neurons, thereby decreasing thresholds andwidening the therapeutic window of the target tissue stimulation.

The foregoing description and examples has been set forth to illustratethe disclosure according to various embodiments and are not intended asbeing unduly limiting. The headings provided herein are fororganizational purposes only and should not be used to limitembodiments. Each of the disclosed aspects and examples of the presentdisclosure may be considered individually or in combination with otheraspects, examples, and variations of the disclosure. In addition, unlessotherwise specified, none of the steps of the methods of the presentdisclosure are confined to any particular order of performance.References cited herein are incorporated by reference in their entirety.

While the methods and devices described herein may be susceptible tovarious modifications and alternative forms, specific examples thereofhave been shown in the drawings and are herein described in detail. Itshould be understood, however, that the embodiments disclosed shouldcover modifications, equivalents, and alternatives falling within thespirit and scope of the various embodiments described herein and theappended claims.

Depending on the embodiment, one or more acts, events, or functions ofany of the algorithms, methods, or processes described herein can beperformed in a different sequence, can be added, merged, or left outaltogether (e.g., not all described acts or events are necessary for thepractice of the algorithm). In some examples, acts or events can beperformed concurrently, e.g., through multi-threaded processing,interrupt processing, or multiple processors or processor cores or onother parallel architectures, rather than sequentially.

The use of sequential, or time-ordered language, such as “then,” “next,”“after,” “subsequently,” and the like, unless specifically statedotherwise, or otherwise understood within the context as used, isgenerally intended to facilitate the flow of the text and is notintended to limit the sequence of operations performed.

The various illustrative logical blocks, modules, processes, methods,and algorithms described in connection with the embodiments disclosedherein can be implemented as electronic hardware, computer software, orcombinations of both. To clearly illustrate this interchangeability ofhardware and software, various illustrative components, blocks, modules,operations, and steps have been described above generally in terms oftheir functionality. Whether such functionality is implemented ashardware or software depends upon the particular application and designconstraints imposed on the overall system. The described functionalitycan be implemented in varying ways for each particular application, butsuch implementation decisions should not be interpreted as causing adeparture from the scope of the disclosure.

The various illustrative logical blocks and modules described inconnection with the embodiments disclosed herein can be implemented orperformed by a machine, such as a general purpose processor, a digitalsignal processor (DSP), an application specific integrated circuit(ASIC), a field programmable gate array (FPGA) or other programmablelogic device, discrete gate or transistor logic, discrete hardwarecomponents, or any combination thereof designed to perform the functionsdescribed herein. A general purpose processor can be a microprocessor,but in the alternative, the processor can be a controller,microcontroller, or state machine, combinations of the same, or thelike. A processor can also be implemented as a combination of computingdevices, e.g., a combination of a DSP and a microprocessor, a pluralityof microprocessors, one or more microprocessors in conjunction with aDSP core, or any other such configuration.

The blocks, operations, or steps of a method, process, or algorithmdescribed in connection with the embodiments disclosed herein can beembodied directly in hardware, in a software module executed by aprocessor, or in a combination of the two. A software module can residein RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory,registers, hard disk, a removable disk, an optical disc (e.g., CD-ROM orDVD), or any other form of volatile or non-volatile computer-readablestorage medium known in the art. A storage medium can be coupled to theprocessor such that the processor can read information from, and writeinformation to, the storage medium. In the alternative, the storagemedium can be integral to the processor. The processor and the storagemedium can reside in an ASIC. The ASIC can reside in a user terminal. Inthe alternative, the processor and the storage medium can reside asdiscrete components in a user terminal.

Conditional language used herein, such as, among others, “can,” “might,”“may,” “e.g.,” and the like, unless specifically stated otherwise, orotherwise understood within the context as used, is generally intendedto convey that some examples include, while other examples do notinclude, certain features, elements, and/or states. Thus, suchconditional language is not generally intended to imply that features,elements, blocks, and/or states are in any way required for one or moreexamples or that one or more examples necessarily include logic fordeciding, with or without author input or prompting, whether thesefeatures, elements and/or states are included or are to be performed inany particular embodiment.

The methods disclosed herein may include certain actions taken by apractitioner; however, the methods can also include any third-partyinstruction of those actions, either expressly or by implication. Forexample, actions such as “positioning an electrode” include “instructingpositioning of an electrode.”

The ranges disclosed herein also encompass any and all overlap,sub-ranges, and combinations thereof. Language such as “up to,” “atleast,” “greater than,” “less than,” “between,” and the like includesthe number recited. Numbers preceded by a term such as “about” or“approximately” include the recited numbers and should be interpretedbased on the circumstances (e.g., as accurate as reasonably possibleunder the circumstances, for example ±5%, ±10%, ±15%, etc.). Forexample, “about 1 hour” includes “1 hour.” Phrases preceded by a termsuch as “substantially” include the recited phrase and should beinterpreted based on the circumstances (e.g., as much as reasonablypossible under the circumstances). For example, “substantiallyperpendicular” includes “perpendicular.” Unless stated otherwise, allmeasurements are at standard conditions including temperature andpressure. The phrase “at least one of” is intended to require at leastone item from the subsequent listing, not one type of each item fromeach item in the subsequent listing. For example, “at least one of A, B,and C” can include A, B, C, A and B, A and C, B and C, or A, B, and C.

What is claimed is:
 1. A system for nerve block of a patient utilizing acapacitive rechargeable electrode, comprising: a current generator; atleast one implantable electrode comprising titanium nitride, the atleast one electrode configured to be in electrical communication withthe current generator; a sensor configured to determine a state ofstored charge of the at least one implantable electrode; and acontroller configured to: generate, by way of signaling to the currentgenerator, a first current with a first polarity proximal to the atleast one electrode sufficient to at least partially block conduction ina nerve, wherein an amount of stored charge in the at least oneelectrode decreases and generates current in an ionic componentproximate the at least one electrode when the electrode is implantedwithin the patient; generate, by way of signaling to the currentgenerator, a second current with a second polarity proximal to the atleast one electrode sufficient to increase the amount of stored chargein the at least one electrode; receive data from the sensor; determineif an amount of water is being electrolyzed; and in response todetermining that the amount of water is being electrolyzed,discontinuing at least one of the first current or the second current.2. The system of claim 1, wherein the decrease and increase in amount ofstored charge on the at least one electrode are not equal.
 3. The systemof claim 1, wherein the at least one electrode is housed in an insulatedenclosure.
 4. The system of claim 1, wherein the titanium nitridecomprises porous or fractal titanium nitride.
 5. The system of claim 1,wherein titanium nitride electrode is configured to deliver at leastabout 25,000 μC of charge into excitable tissue without damaging theexcitable tissue.
 6. The system of claim 1, wherein the system is devoidof any mechanically moving parts.
 7. The system of claim 1, whereintitanium nitride electrode is configured to deliver at least about 5,000μC of charge into excitable tissue without damaging the excitabletissue.
 8. A system for nerve block of a patient utilizing a capacitiverechargeable electrode, comprising: a current generator; at least oneimplantable electrode comprising a high charge density materialconfigured to be spaced apart from a nerve interface by an ioniccomponent, the at least one implantable electrode configured to be inelectrical communication with the current generator; and a controllerconfigured to signal the current generator to: generate a first currentwith a first polarity proximal to the at least one implantable electrodesufficient to at least partially block conduction in a nerve, wherein anamount of stored charge in the at least one electrode decreases andgenerates current in an ionic component proximate the at least oneelectrode when the electrode is implanted within the patient; andgenerate a second current with a second polarity proximal to the atleast one implantable electrode sufficient to increase the amount ofstored charge of the at least one implantable electrode; wherein thefirst current comprises a smooth trapezoidal waveform that ramps up to atarget anodic magnitude and ramps down to a target cathodic magnitudesuch that transitions between ramp regions and plateaus of the smoothtrapezoidal waveform comprise a smoothing function.
 9. The system ofclaim 8, further comprising a sensor configured to determine the stateof charge of the at least one implantable electrode, wherein thecontroller is further configured to receive data from the sensor anddiscontinue at least one of the first current or the second current whenan amount of water is being electrolyzed.
 10. The system of claim 8,wherein the decrease and increase in amount of stored charge on the atleast one electrode are not equal.
 11. The system of claim 8, whereinthe at least one implantable electrode is configured to deliver at leastabout 5,000 μC of charge into excitable tissue without damaging theexcitable tissue.
 12. The system of claim 8, wherein the at least oneimplantable electrode is configured to deliver at least about 25,000 μCof charge into excitable tissue without damaging the excitable tissue.13. The system of claim 8, wherein the system is devoid of anymechanically moving parts.
 14. The system of claim 8, wherein the atleast one implantable electrode is at least partially surrounded by anelectrolyte solution.
 15. The system of claim 8, wherein the high chargedensity material comprises titanium nitride.
 16. The system of claim 8,wherein the controller is configured to maintain the nerve in ahypersuppressed state at least partially preventing conduction of thenerve for at least about 10 minutes after cessation of delivering of thefirst current.
 17. The system of claim 9, wherein the smoothing functioncomprises a cubic hermite spline.
 18. The system of claim 9, wherein thesmoothing function comprises at least first derivative continuity. 19.The system of claim 8, wherein the ramp regions comprise leading rampregions that approach plateaus and trailing ramp regions that trailplateaus, the leading ramp regions comprising a ramp rate that is lowerthan a ramp rate of the trailing ramp regions.